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Theranostics, integrating diagnostic and therapeutic functionalities, have emerged as advanced systems for timely cancer diagnosis and effective treatment. The development of versatile materials suitable for cancer theranostics is intensifying. Porphyrin-based metal-organic frameworks (MOFs) leverage the structural diversity and designability inherent in MOFs, alongside the robust photophysical, catalytic, and biological properties of porphyrins. These materials enhance the solubility and stability of porphyrins and facilitate their stable functionalized assemblies, conferring the potential for multimodal imaging diagnostics and precision therapeutics. In this review, we summarized the potential of porphyrin-based MOFs as cancer theranostics platforms, focusing on recent advancements in porphyrin-based MOFs, and highlighting their functionalized strategies and developments in diagnostic imaging and synergistic therapies. Finally, we proposed the challenges and prospects of these emerging materials in cancer theranostics.

Triple-negative breast cancer (TNBC) with high postoperative recurrence rate and aggressive invasiveness remains a significant threat to women. Here, we developed an engineered-exosome disguised multifunctional nanoplatform (IG Exo-Lipo) utilizing engineered exosomes mixed with liposomes as carriers, encapsulating both IR780 and gambogic acid prodrug (MPEG-TK-GA), to enhance the efficacy of chemo-photothermal therapy for the treatment of TNBC. The disguise of SIRPα gene engineered-exosome endowed IG Exo-Lipo with low immunogenicity, long circulation time, and innate targeting capability. Upon entering tumor cells, the loaded IR780 in the IG Exo-Lipo mediated low-temperature photothermal therapy (PTT) and generated reactive oxygen species (ROS) under NIR light irradiation. Immediately, gambogic acid was released on-demand by MEPG-TK-GA cleaving under the stimulation of ROS, allowing for low-dose chemotherapy while simultaneously enhancing low-temperature PTT through the downregulation of heat shock protein 90. In vitro and in vivo antitumor evaluations indicated that IG Exo-Lipo improved therapeutic efficacy significantly by synergistic enhancement of chemo-photothermal therapy. Overall, the engineered-exosome disguised multifunctional nanoplatform enabled an enhanced chemo-photothermal treatment of TNBC, showing promising clinical application potential.

Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH2) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment.

Carrier-free nanomedicine represents a new opportunity of using less inert materials for efficient drug delivery. To date, most reported carrier-free nanomedicine systems rely heavily on π-π stacking interaction between hydrophobic drugs. This work found that the hydrophilic IR783 dye can collaborate with the hydrophobic curcumin (Cur) compound to form a novel Cur@IR783 nanocolloid (NC) via self-assembly. The self-assembly of the hydrophilic IR783 and hydrophobic Cur improved the water dispersity of Cur, significantly facilitating its administration in vivo. Moreover, Cur@IR783 NC retained the IR783 properties of NIR fluorescence and photothermal conversion efficiency. Fluorescence imaging demonstrated that Cur@IR783 NC accumulated at the tumor site via the enhanced permeation and retention effect, which ensured enhanced anti-tumor effect. In vitro and in vivo experiments showed that the Cur@IR783 NC with laser irradiation yielded the most potent antitumor effect, and Cur@IR783 NC exhibited high biocompatibility. Overall, Cur@IR783 NC showed remarkable synergistic antitumor activity via chemo-photothermal combination therapy, providing a new promising approach for Cur-based applications in cancer treatment.

Several diseases, such as cancer, are not controlled by a single factor and nanotherapeutic derived from multiple bioactive ingredients of natural products (NMBINP) has shown promise therapeutical results recently. Traditional Chinese medicine (TCM) is a therapeutic system, wherein mixtures of natural products mostly act synergistically to modulate multiple targets. Its therapeutic efficacy has been demonstrated in several disease conditions. Despite the unknown panoramic composition and impurity toxicity of TCM, screening for bioactive ingredients from TCM is still a good path for drug discovery owing to its narrow scope. NMBINP is a TCM-inspired nanomedicine established based on the two major advantages of TCM: (1) screening pharmaceutically active molecules from natural products and (2) achieving effective synergistic therapy with multiple targets. Recently, the isolation of bioactive ingredients from TCM and their delivery using nanoparticles have been extensively developed against diverse diseases. NMBINP possesses synergistic therapeutic features of TCM with multiple identified ingredients and its verifiable efficacy demonstrates bright prospects. Further NMBINP exploration can create more effective therapeutics and contribute to better TCM development as NMBINP takes root in TCM. The current review discusses the strengths and deficiencies of TCM, the development of bioactive ingredients isolated from TCM, and NMBINP as a robust tool for developing traditional medicine. Finally, this article is summarized and future perspectives of NMBINP are discussed.

Recently, microgel-based drug delivery systems have received great attention. However, these systems face various challenges such as low drug loading, leakage, rapid drug elimination by the bloodstream, and low efficacy against tumors. To overcome these limitations, we fabricated a near-infrared (NIR)-responsive poly(N-isopropylacrylamide-co-acrylic acid)/Prussian blue microgel (PNA@PB). The microgel featured improved stability and higher loading of Prussian blue (PB), achieved by chemically linking it to the polymer. For cancer therapy, the microgel was loaded with the model drug doxorubicin (DOX) to obtain PNA@PB@DOX, resulting in a high loading capacity of 26% and encapsulation efficiency of 51%. Upon exposure to 808 nm NIR laser light, the photothermal PB in PNA@PB@DOX raised the temperature above the lower critical solution temperature of the microgel, causing the microgel to shrink and release the drug by 36%. The NIR-triggered drug release by PNA@PB@DOX resulted in improved photothermal/chemotherapy performance, both in vitro and in vivo experiments using A549 lung cancer cells, compared with PNA@PB. The combination of photothermal therapy from PB and photothermal shrinkage-induced chemotherapy from PNA was found to be highly effective in killing cancer cells.

The accurate diagnosis and effective therapy of malignant tumors is still a challenge owing to its poor prognosis, recurrence, and drug resistance. In this study, a tumor microenvironment responsive and high O2-economic effect nano-theranostic agent GOx@NPs was constructed through the self-assembly of GOx and CDDO-Fe, which was synthesized by coupling natural chemotherapeutic drug CDDO-Me blocked by ferrocene (Fc) with near-infrared (NIR) fluorescence probe hemicyanine (I-CyOH) via redox-responsive linker dimercaptoisopropionyl, and then introducing tamoxifen (estrogen receptor target fragment) to hemicyanine to enhance the active targeting ability. The NIR fluorescence probe I-CyOH not only achieved an accurate diagnosis, but also possessed photodynamic therapy (PDT) effect. The active targeting fragment tamoxifen enhanced the accumulation of pathological site and alleviated the hypoxia microenvironment through the inhibition of mitochondrial respiratory to reinforce the PDT efficiency of I-CyOH. Moreover, the combination of Fc and GOx could achieve starvation therapy and enhance chemodynamic therapy (CDT). In vitro and vivo experiments exhibited that the effective dual sensitive synergistic therapy possessed significant therapy efficiency and lower side effects. This study provides a valuable strategy for constructing dual sensitization and high economic of intelligent nano-theranostic agents for tumor diagnosis and synergistic cancer therapy.

Cisplatin is a metal platinum complex commonly used in the field of anti-tumor and one of the most commonly used drugs in combination chemotherapy. However, chemotherapy with Cisplatin induced overexpression of cyclooxygenase-2 (COX-2) protein in tumor cells, which could impair the therapeutic effect of chemotherapy on tumor progression. Here, we presented a novel method for the treatment of ovarian cancer with a self-assembly based nano-system. Cisplatin and tolfenamic acid were each linked to linoleic acid to give them the ability to self-assemble into nanoparticles in water. TPNPs had flexible drug ratio adjustability, homogeneous stability, and high drug loading capacity. Compared with Cisplatin, TPNPs could promote cellular uptake and tumor aggregation, co-induce enhanced apoptosis and tumor growth inhibition by inhibiting COX-2 in the mice xenograft model of human ovarian cancer, and reduce systemic toxicity. Therefore, TPNPs is a promising antitumor drug as a kind of self-assembly nano-prodrug with high drug load.

Tumor microenvironment (TME) with the particular features of severe hypoxia, insufficient endogenous H2O2, and overexpression of glutathione (GSH) markedly reduced the antitumor efficacy of monotherapy. Herein, a TME-responsive multifunctional nanoplatform (Bi2S3@Bi@PDA-HA/Art NRs) was presented for synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and photodynamic therapy (PDT) to achieve better therapeutic outcomes. The Z-scheme heterostructured bismuth sulfide@bismuth nanorods (Bi2S3@Bi NRs) guaranteed excellent photothermal performance of the nanoplatform. Moreover, its ability to produce O2 and reactive oxygen species (ROS) synchronously could relieve tumor hypoxia and improve PDT outcomes. The densely coated polydopamine/ammonium bicarbonate (PDA/ABC) and hyaluronic acid (HA) layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ “bomb-like” release of Art. The CDT treatment was achieved by activating the released Art through intracellular Fe2+ ions in an H2O2-independent manner. Furthermore, decreasing the glutathione peroxidase 4 (GPX4) levels by Art could also increase the PDT efficiency of Bi2S3@Bi NRs. Owing to the synergistic effect, this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo. Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.

Bone defects and tumor cell residues after bone tumor resection have always been a challenge. We tried to investigate a kind of bioglass with both bone repair and tumor killing capability to achieve two birds with one stone. We used a Sol-Gel method to prepare the high porous magnetic bioglass (MBG) and then compounded the MBG with calcium sulfate (CS) bone cement to form the composite scaffold (CS-MBG). We found that the CS-MBG could reach about 43 °C under the condition of magnetic field in vitro. Under this condition, CS-MBG would release Ca2+ resulting in the cell death of calcium overload. Meanwhile, the suitable pH and osteogenic activity of CS-MBG can promote the postoperative bone repair and inhibit the growth of bone tumors. Our work has innovatively designed a magnetic bioglass and verified its mechanism of synergistic hyperthermia against tumor, providing a new idea for the treatment of tumor bone defects with magnetic bioglass.

Angiogenesis plays a vital role in the treatment of full-thickness wounds. Deferoxamine (DFO) has been employed to promote neovascularization, however, smart drug delivery systems are needed to optimize its utilization. In this study, an injectable extracellular matrix (ECM)-mimicking hydrogel (HOG@P&D) was developed by leveraging the dynamic Schiff base and hydrogen bonds among a chitosan derivative (HACC), oxidized alginate (OSA), gelatin, and DFO-loaded polydopamine nanoparticles (P&D) for efficient wound healing. The incorporation of P&D enables HOG@P&D to respond to near-infrared (NIR) irradiation, converting laser energy into heat to trigger an on-demand, rapid release of DFO, thereby effectively enhancing angiogenesis. In vitro tube formation assays revealed that the number of meshes in the HOG@P&D group was fourfold higher than that of the control group. Additionally, HOG@P&D exhibited superior mechanical properties, tissue adhesion, and injectability, allowing it to cover wounds seamlessly. This hydrogel also demonstrated antibacterial and antioxidant properties, creating a conducive microenvironment for wound healing. In vivo studies further confirmed that HOG@P&D promoted angiogenesis and mitigated inflammation by upregulating angiogenic growth factor expression, thereby accelerating full-thickness wound healing. This nanocomposite hydrogel shows significant potential as a high-performance wound dressing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu 0 -based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Amalgamation of near-infrared laser phototherapies with chemotherapy in multi-modal synergistic therapy holds great promise for future precision cancer nanomedicine due to its minimal invasiveness, reduced adverse reactions, and high anticancer efficacy. Herein, CuO nanoparticles were functionalized with photosensitizer molecule, chlorin e6 (Ce6) and coated with polydopamine (PDA) to achieve a drug delivery system (CuO@Ce6-PDA) with photothermal/photodynamic therapy (PTT/PDT). Subsequently, chemical drug PTX was loaded for chemotherapy, and folic acid (FA) serving as cancer-targeting exterior material. Prepared FA@CuO@Ce6-PDA/PTX nanoparticles were nano-sized with favorable biocompatibility, colloidal stability, optimal surface charge, effective PTX loading, and controllable PTX release. In vitro studies on 4T1 cells showed that FA@CuO@Ce6-PDA/PTX had noteworthy synergistic therapeutic antitumour effects featuring chemo/PTT/PDT with IC 50 of 50 μg/mL lower than that FA@CuO@Ce6-PDA/PTX without NIR laser irradiation (225 μg/mL). Additionally, FA@CuO@Ce6-PDA/PTX produced intracellular high reactive oxygen species (ROS) in presence of 660 nm laser, altering mitochondrial membrane potential and promoting tumour cell death. In vivo results indicate nanoplatform could accumulate in tumour spots enabling thermal imaging capabilities and exhibit synergistic therapeutic effect if irradiated with NIR laser (808 and 660 nm), evident from in vitro antitumour assay. Therefore, in vitro finding postulates FA@CuO@Ce6-PDA/PTX could be an intriguing nanoplatform for Chemo/PTT/PDT-based combination therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multifunctional nanomedicine has offered a promising strategy for effective anticancer therapy owing to its versatile capabilities. However, the systematic precise delivery still remains intractable challenge because of the existence of multi-staged biological barriers after intravenous administration. Herein, to address this issue, injectable and TME-responsive nanocomposite hydrogels were developed for localized and synergistic cancer therapy. The nanocomposite hydrogels (Au NBPs&Pt NCs@DOX gel) were synthesized via the formation of metal-sulfur bonds between 4arm-PEG-thiol and Au nanobipyramids or Pt nanoclusters with the DOX encapsulation. The hydrogel exhibited rapid gelation and excellent injectability. Attributed to the high absorbance of Au NBPs, the nanocomposite hydrogels revealed superior photothermal effect under NIR irradiation, which the DOX release was also regulated by NIR laser. In addition, the catalase- and peroxidase-like activities of Pt NCs were validated to convert endogenous H2O2 into ROS and O2 in situ to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Simultaneously, catalytic therapy combined with NIR irradiation exhibited strongest inhibition to the growth of 4T1 tumor in vitro and in vivo. Thus, this study provided a new strategy for TME remodeling and local combination therapies of different therapeutic agents.

The booming photothermal therapy (PTT) has achieved great progress in non-invasive oncotherapy, and paves a novel way for clinical oncotherapy. Of note, mild temperature PTT (mPTT) of 42–45 °C could avoid treatment bottleneck of the traditional PTT, including nonspecific injury to normal tissues, vasculature and host antitumor immunity. However, cancer cells can resist mPTT via heat shock response and autophagy, thus leading to insufficient mPTT monotherapy to ablate tumor. To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT, synergistic therapies towards cancer cells have been conducted with mPTT. This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment, including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies. Moreover, challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H2O2) as starvation therapy. Fenton reaction involving the regenerated H2O2 in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer (HNC). Conventional treatment of HNSCC involves surgical removal, together with or without chemoradiotherapy. Because of the special location of head and neck tumors, trauma of surgical intervention often impairs physiological functions and causes disfigurement, seriously affecting the quality of life of HNSCC patients. High levels of reactive oxygen species (ROS) have been reported to cause cancer cell death by inducing apoptosis, autophagy, necroptosis and ferroptosis. Based on this, some non-invasive nanotherapeutics have aroused considerable attention, which could promote the generation of ROS with or without external stimuli, damaging biological macromolecules to kill cancer cells. Herein, the authors present the mechanisms of ROS-based cancer therapy and summarize different nanotherapeutics against HNSCC, including photodynamic therapy (PDT), sonodynamic therapy (SDT), radiation therapy (RT), and chemodynamic therapy (CDT). Furthermore, ROS-sensitive drug release nanosystems and some synergistic therapeutic modalities for HNSCC are reviewed. Finally, challenges and future perspectives of these treatments are also discussed for further research directions, which can facilitate the development of ROS-based nanotherapeutics for clinical application.

Targeted delivery of therapeutic agents to malignant tumor sites is an effective strategy to improve the treatment outcomes for tumor precise therapy. Herein, based on the abnormal tumor metabolism (glutamine addiction), a nanosystem of glutamine-decorated nanoparticles was fabricated to achieve efficient tumor delivery. Considering the high toxicity and side effect by chemotherapy with high doses, a chemotherapeutic sensitizer tetrandrine was used in combination with doxorubicin to achieve a synergistic effect in tumor treatment. The targeted nanosystems of glutamine-decorated nanoparticles (GDTNPs) were loaded with doxorubicin and tetrandrine simultaneously. Effective tumor accumulation of GDTNPs in vitro and in vivo was achieved due to glutamine addiction and the extraordinary inter-organ glutamine metabolism. The data revealed that tetrandrine enhanced the efficacy of doxorubicin to hepatic carcinoma cells by blocking cell proliferation, inducing apoptosis, and arresting cell cycle, demonstrating the synergism of doxorubicin and tetrandrine. With KM mice bearing murine hepatic tumor (H22) as model, GDTNPs demonstrated the optimum tumor inhibition efficacy with no notable systemic toxicity. Therefore, it could be propose that the co-delivery of doxorubicin and tetrandrine by the glutamine-decorated nanoparticles is a promising strategy for the effective chemotherapy of hepatic carcinoma with enhanced efficacy and reduced cytotoxicity.

A graphene quantum dots (GQDs) and manganese dioxide (MnO2) co-decorated, polydopamine (PDA) capped iron oxyhydroxide (FeOOH) nanorod was firstly constructed as a promising platform for magnetic resonance imaging (MRI) guided tumor synergistic therapy. Each component played an irreplaceable role. Tumor microenvironment activated cascade Fenton catalytic activities and MRI capability at different stages were obtained, which can simultaneously realize diagnosis and chemodynamic therapy (CDT) for cancer. In addition, photothermal therapy (PTT) was also achieved owing to the excellent photothermal conversion efficiency of PDA and GQDs, which further improve the Fenton catalytic activities and realized synergistic therapy for cancer. The experimental results showed that only about 30% of cancer cells was killed when CDT or NIR laser alone for cancer inhibition. However, when PTT and CDT were employed simultaneously to treat the cancer cells, the therapeutic efficiency has increased by 300% (90% of cancer cells was killed and about 10% cancer cells survived) due to combinatorial effect of PTT and CDT. Obviously, a more effective treatment of cancer could be realized using MRI guided tumor synergistic therapy with the as-prepared nanocomposites. This study provides a proof of concept of design and construction of complex nanomaterials for cancer diagnosis and treatment.

The BCL-XL-selective inhibitors exhibit potential clinical application value when combined with chemotherapeutic drugs for the treatment of solid tumors. However, their efficacy in these settings is still low when treated with BCL-XL inhibitors alone in solid tumors. The mechanism responsible for the poor efficacy remains unclear. We show here that unable to interact with target of BCL-XL-selective inhibitors caused by invalid entry into mitochondria is essential for their inefficacy in solid tumors. We demonstrated in non-small-cell lung cancer (NSCLC) cells that the instability of A-1155463 in cells as well as invalid entry into mitochondria of A-1331852, two BCL-XL-selective inhibitors, accounted for their off-target problems. Furthermore, we found that a mitochondria-targeted, non-toxic small molecule NA-2a improved the on-target effect of A-1331852 to enhance its apoptotic regulatory activity, thereby increasing its anticancer activity in NSCLC. Our results indicated that NA-2a was selectively enriched in mitochondria transported by organic-anion-transporting polypeptide (OATP) transporters, which altered the permeability of the mitochondrial membrane, thereby promoting the entrance of A-1331852 to mitochondria and enhancing its disruption of the BIM-BCL-XL complex, which finally led to the increased anticancer activity in vitro and in vivo. Collectively, our data provided overwhelming evidence that the combination of NA-2a and A-1331852 could be used as a promising synergistic therapeutic agent in NSCLC therapy.

B-cell lymphoma has a poor prognosis due to difficulties in early diagnosis and the negative effects of systemic chemotherapy. Therefore, there is an urgent need to develop highly accurate and effective theranostic strategies for B-cell lymphoma. In this study, we designed a poly (lactic-co-glycolic acid) (PLGA)-based theranostic nanoplatform (denoted as TscNPs) to achieve ultrasound (US)/magnetic resonance (MR) bimodal imaging-guided photothermal (PTT)/chemo synergistic therapy of B-cell lymphoma. The nanoplatform was conjugated with a CD20 monoclonal antibody specifically targeting B-cell lymphoma to promote tumor accumulation. Encapsulated superparamagnetic iron oxide nanoparticles (SPIONs) as photothermal and MR imaging agents enabled thermal ablation of tumors and imaging-guided tumor therapy. When exposed to near-infrared (NIR) laser, TscNPs generate heat that induces optical droplet vaporization (ODV) of perfluoropentane (PFP), which transforms into microbubbles. This process not only enhanced ultrasound imaging, but also facilitated the release of celastrol (CST) from the nanoplatform, ultimately achieving a PTT/chemo synergistic therapy effect. In the tumor-bearing nude mice model, TscNPs were effectively accumulated in the tumor region. Furthermore, the combined treatment mode of TscNPs and NIR laser irradiation demonstrated a tumor inhibition rate of approximately 96.57 %, which was significantly superior to the rates observed with PTT or chemotherapy alone. These results suggest that the multifunctional theranostic nanoplatform represents a promising new strategy for the therapy of B-cell lymphoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Hypoxia and high concentration of glutathione (GSH) in tumor seriously hinder the role of reactive oxygen species (ROS) and oxygen-dependence strategy in tumor treatment. In this work, a self-generating oxygen and self-consuming GSH hyaluronic acid (HA)-coated porphyrin nanoplatform (TAPPP@CaO 2 /Pt(IV)/HA) is established for enhancing photodynamic/ion/chemo targeting synergistic therapy of tumor. During the efforts of ROS production by nanosystems, a GSH consuming strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. CaO 2 in the nanosystems is decomposed into O 2 and H 2 O 2 in an acidic environment, which alleviates hypoxia and enhances the photodynamic therapy (PDT) effect. Calcium overload causes mitochondria dysfunction and induces apoptosis. Pt (IV) reacts with GSH to produce Pt (II) for chemotherapy and reduce the concentration of GSH, protecting ROS from scavenging for augmenting ROS-induced oxidative damage. In vitro and in vivo results demonstrated the self-generating oxygen and self-consuming GSH strategy can enhance ROS-dependent PDT coupled with ion/chemo synergistic therapy. The proposed strategy not only solves the long-term problem that hypoxia limits therapeutic effect of PDT, but also ameliorates the highly reducing environment of tumors. Thus the preparation of TAPPP@CaO 2 /Pt(IV)/HA provided a novel strategy for the effective combined therapy of cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu + efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu 2 O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu + . The liberated Cu + triggered a Fenton-like reaction for CDT and partially transformed to Cu 2+ , consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors.)

The last few years have witnessed explosive growth in the design and development of various photothermal agents (PTAs) to realize phtothermal therapy (PTT) for eradicating solid tumors. Nevertheless, the therapeutic efficacy of PTT is still restricted by several obstacles, especially the thermotolerance of tumors, which might potentially induce inflammatory disease, damage normal organs, or even lead to tumor recurrence. Exploitation of innovative strategies to enhance PTT at mild temperature is thus the key determinant toward successful clinical use of PTT. In this review, we dissect the cell death mechanism triggered by PTT at different temperature, indicating that enhancing apoptosis pathway is favorable for PTT at mild temperature. The recent advances in the construction of mild-temperature PTT through regulating heat shock proteins expression, autophagy level, free radical generation and organelle targeting to overcome tumor thermotolerance are susequently concluded, along with the excellent and representative examples of combining mild-temperature PTT with other therapies (i.e. photodynamic therapy, chemodynamic therapy, starvation therapy and gas therapy), which exhibits the remarkable superadditive effect. Furthermore, the key scientific and technical challenges for mild-temperature PTT are also discussed to accelerate clinical translation.

The synthesis of a novel versatile nanomedicine platform integrating multiple imaging and therapeutic functions has always been a great challenge for efficient cancer diagnosis and therapy. Herein, in this study, a novel versatile carbon monoxide (CO) delivery nanoplatform was constructed with hollow mesoporous CuS NPs carrying manganese carbonyl (MnCO) to realize MR imaging-guided PTT and CO combined anticancer therapy. The MnCO@CuS nanoplatform revealed superior properties in colloidal stability, photothermal conversion, H2O2/NIR-stimulated CO release and tumoral accumulation. More importantly, the enriched H2O2 in the tumor microenvironment (TME) triggered MnCO to release CO in situ, and this process was further strengthened by the NIR irradiation. Subsequently, the intermediate products MnOx was degraded into Mn2+ by the mild acidic tumor microenvironment to enable T1-weighted MR imaging. Simultaneously, the in situ-released CO combined with NIR irradiation exhibited strongest inhibition to the growth of MV3 tumor in vitro and in vivo. Moreover, the multifunctional nanoplatform also exhibited low toxicity and good biocompatibility in vitro and in vivo. Hence, these results suggested the MnCO@CuS nanoplatform possessed significant potential in realizing TME/NIR stimulated CO/Mn2+ generation and photothermal conversion for MR imaging-guided synergistic PTT and CO anticancer therapy.

Photoactivated therapy has gradually emerged as a promising and rapid method for combating bacteria, aimed at overcoming the emergence of drug-resistant strains resulting from the inappropriate use of antibiotics and the subsequent health risks. In this work, we report the facile fabrication of Zn 3 [Fe(CN) 6 ]/g-C 3 N 4 nanocomposites (denoted as ZHF/g-C 3 N 4 ) through the in-situ loading of zinc hexacyanoferrate nanospheres onto two-dimensional g-C 3 N 4 sheets using a simple metal-organic frameworks construction method. The ZHF/g-C 3 N 4 nanocomposite exhibits enhanced antibacterial activity through the synergistic combination of the excellent photothermal properties of ZHF and the photodynamic capabilities of g-C 3 N 4 . Under dual-light irradiation (420 nm + 808 nm NIR), the nanocomposites achieve remarkable bactericidal efficacy, eliminating 99.98% of Escherichia coli and 99.87% of Staphylococcus aureus within 10 minutes. Furthermore, in vivo animal experiments have demonstrated the outstanding capacity of the composite in promoting infected wound healing, achieving a remarkable wound closure rate of 99.22% after a 10-day treatment period. This study emphasizes the potential of the ZHF/g-C 3 N 4 nanocomposite in effective antimicrobial applications, expanding the scope of synergistic photothermal/photodynamic therapy strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) has become a promising approach and non-invasive modality for cancer treatment, however the therapeutic effect of PDT is limited in tumor metastasis and local recurrence. Herein, a tumor targeted nanomedicine (designated as PCN@HA) is constructed for enhanced PDT against tumors. By modified with hyaluronic acid (HA), which could target the CD44 receptor that expressed on the cancer cells, the targeting ability of PCN@HA has been enhanced. Under light irradiation, PCN@HA can produce cytotoxic singlet oxygen ( 1 O 2 ) and kill cancer cells, then eliminate tumors. Furthermore, PCN@HA exhibits fluorescence (FL)/ photoacoustic (PA) effects for multimodal imaging-guided cancer treatment. And PCN@HA-mediated PDT also can induce immunogenic cell death (ICD) and stimulate adaptive immune responses by releasing of tumor antigens. By combining with anti-PD-L1 checkpoint blockade therapy, it can not only effectively suppress the growth of primary tumor, but also inhibit the metastatic tumor growth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stroke poses a serious risk to the physical and mental health of patients. Endogenous compounds are widely used to treat ischemic stroke. Lipoic acid, a naturally occurring (R)-5-(1,2-dithiolan-3-yl)pentanoic acid, has therapeutic potential for the treatment of ischemic stroke. However, the direct application of lipoic acid is limited by its relatively low efficacy and instability. Therefore, there is a need to modify the structure of lipoic acid to improve its pharmaceutical capabilities. Currently, 37 lipoic acid derivatives have been synthesized, and compound AA-9 demonstrated optimal therapeutic potential in an in vitro model of induced oxidative damage using tert-butyl hydroperoxide (t-BHP). In addition, in vitro experiments have shown that compound AA-9 has an excellent safety profile. Subsequently, the therapeutic effect of AA-9 was significant in the rat MCAO ischemic stroke model, which may be attributed to the antioxidant and anti-inflammatory effects of compound AA-9 by activating PGC-1α and inhibiting NLRP3. Notably, compound AA-9 exhibited higher stability and better bioavailability properties than ALA in plasma stability and pharmacokinetic properties. In conclusion, AA-9 may be a promising neuroprotective agent for the treatment of ischemic stroke and warrants further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe 2 O 4 @NaGdF 4 @NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe 2 O 4 @NaGdF 4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H 2 O 2 , which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn 2+ -activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. STATEMENT OF SIGNIFICANCE: The Janus structured MnFe 2 O 4 @NaGdF 4 @NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe 2 O 4 @NaGdF 4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn 2+ -mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Sonodynamic therapy (SDT), utilizing ultrasound (US) as the trigger, has gained popularity recently as a therapeutic approach with significant potential for treating various diseases. Metal-organic frameworks (MOFs), characterized by structural flexibility, are prominently emerging in the SDT realm as an innovative type of sonosensitizer, offering functional tunability and biocompatibility. However, due to the inherent limitations of MOFs, such as low reactivity to reactive oxygen species and challenges posed by the complex tumor microenvironment, MOF-based sonosensitizers with singular functions are unable to demonstrate the desired therapeutic efficacy and may pose risks of toxicity, limiting their biological applications to superficial tissues. MOFs generally possess distinctive crystalline structures and properties, and their controlled coordination environments provide a flexible platform for exploring structure-effect relationships and guiding the design and development of MOF-based nanomaterials to unlock their broader potential in biological fields. The primary focus of this paper is to summarize cases involving the modification of different MOF materials and the innovative strategies developed for various complex conditions. The paper outlines the diverse application areas of functionalized MOF-based sonosensitizers in tumor synergistic therapies, highlighting the extensive prospects of SDT. Additionally, challenges confronting SDT are briefly summarized to stimulate increased scientific interest in the practical application of MOFs and the successful clinical translation of SDT. Through these discussions, we strive to foster advancements that lead to early-stage clinical benefits for patients. STATEMENT OF SIGNIFICANCE: 1. An overview for the progresses in SDT explored from a novel and fundamental perspective. 2. Different modification strategies to improve the MOFs-mediated SDT efficacy are provided. 3. Guidelines for the design of multifunctional MOFs-based sonosensitizers are offered. 4. Powerful tumor ablation potential is reflected in SDT-led synergistic therapies. 5. Future challenges in the field of MOFs-based SDT in clinical translation are suggested., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Theranostic nanoplatforms with integrated diagnostic imaging and multiple therapeutic functions play a vital role in precise diagnosis and efficient treatment for breast cancer, but unfortunately, these nanoplatforms are usually stuck in single-site imaging and single mode of treatment, causing unsatisfactory diagnostic and therapeutic efficiency. Herein, a dual biomarkers-activatable facile hollow mesoporous MnO 2 (H-MnO 2 )-based theranostic nanoplatform, DNAzyme@H-MnO 2 -MUC1 aptamer (DHMM), was constructed for the simultaneous multi-site diagnosis and multiple treatment of breast cancer., Results: The DHMM acted as an integrated diagnostic and therapeutic nanoplatform that realizes multi-site fluorescence imaging-guided high-efficient photothermal/chemodynamic/gene synergistic therapy (PTT/CDT/GT) for breast cancer. The H-MnO 2 exhibits high loading capacity for Cy5-MUC1 aptamer (3.05 pmoL μg -1 ) and FAM-DNAzyme (3.37 pmoL μg -1 ), and excellent quenching for the probes. In the presence of MUC1 on the cell membrane and GSH in the cytoplasm, Cy5-MUC1 aptamer and FAM-DNAzyme was activated triggering dual-channel fluorescence imaging at different sites. Moreover, the self-supplied Mn 2+ was further supplied as DNAzyme cofactors to catalytic cleavage intracellular EGR-1 mRNA for high-efficient GT and stimulated the Fenton-like reaction for CDT. The H-MnO 2 also showcases a favorable photothermal performance with a photothermal conversion efficiency of 44.16%, which ultimately contributes to multi-site fluorescence imaging-guided synergistic treatment with an apoptosis rate of 71.82%., Significance: This dual biomarker-activatable multiple therapeutic nanoplatform was realized multi-site fluorescence imaging-guided PTT/CDT/GT combination therapy for breast cancer with higher specificity and efficiency, which provides a promising theranostic nanoplatform for the precision and efficiency of breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Highly toxic reactive oxygen species (ROS), crucial in inducing apoptosis and ferroptosis, are pivotal for cell death pathways in cancer therapy. However, the effectiveness of ROS-related tumor therapy is impeded by the limited intracellular ROS and substrates, coupled with the presence of abundant ROS scavengers like glutathione (GSH). In this research, we developed acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating a mitochondrial-targeting drug alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment. The imidazole grafted micelles exhibit prolonged blood circulation and improve the delivery efficiency of the hydrophobic drug α-TOS. Additionally, PPA's design aids in delivering Fe 3+ , supplying ample iron ions for chemodynamic therapy (CDT) and ferroptosis through the attachment of imidazole groups to Fe 3+ . In the tumor's weakly acidic intracellular environment, PPA/TF facilitates pH-responsive drug release. α-TOS specifically targets mitochondria, generating ROS and replenishing those depleted by the Fenton reaction. Moreover, the presence of Fe 3+ in PPA/TF amplifies ROS upregulation, promotes GSH depletion, and induces oxidative damage and ferroptosis, effectively inhibiting tumor growth. This research presents an innovative ROS-triggered amplification platform that optimizes CDT and ferroptosis for effective cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Both ursolic acid (UA) and sorafenib (Sora) have been generally utilized in cancer treatment, and the combination of the two has also shown a good anti-tumor effect. However, single-agent therapy for Hepatocellular carcinoma (HCC) has the disadvantages of multi-drug resistance, poor water solubility and low bioavailability, and the application of traditional nanocarrier materials is limited due to their low drug loading and low carrier-related toxicity. Therefore, we prepared US NPs with different proportions of UA and Sora by solvent exchange method for achieving synergistic HCC therapy. US NPs had suitable particle size, good dispersibility and storage stability, which synergistically inhibited the proliferation of HepG2 cells, SMMC7721 cells and H22 cells. In addition, we also proved that US NPs were able to suppress the migration of HepG2 cells and SMMC7721 cells and reduce the adhesion ability and colony formation ability of these cells. According to the results, US NPs could degrade the membrane potential of mitochondrial, participate in cell apoptosis, and synergistically induce autophagy. Collectively, the carrier-free US NPs provide new strategies for HCC treatment and new ideas for the development of novel nano-drug delivery systems containing UA and Sora., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In photothermal therapy (PTT) and chemodynamic therapy (CDT) of cancer, poor performance of nanoagents severely impaired the therapeutic effect of cancer. To solve the problem, we proposed and constructed a novel Mn doped Cu 7 S 4 phothermal nanoagent both in the first near-infrared (NIR-I) and the second near- infrared (NIR-II) windows in this work, which exhibited high photothermal conversion efficiency of 40.3% at 808 nm (NIR-I window) and 33.4% at 1064 nm (NIR-II window), as well as outstanding pH-sensitive catalytic performance (peroxidase-like catalytic activity and Fenton-like catalytic activities). The as-prepared Mn doped Cu 7 S 4 could be used to load chemotherapy drug doxorubicin (DOX) after modified by folic acid. Both in vitro and in vivo studies indicated that it could be used as nanoagent for chemodynamic therapy (CDT)/photothermal therapy (PTT)/ chemotherapy of cervical carcinoma. This study thus provided an NIR-I/NIR-II/pH responsive nanoagent for potential synergistic therapy of deep-seated tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Combination chemotherapy is a common strategy to enhance treatment efficacy and avoid multidrug resistance (MDR) in clinical practice. However, it is difficult to ensure the co-enrichment and reasonable ratio of synergistic drugs in the lesion site after intravenous administration. Integrating synergistic drugs into a nanocarrier can improve drug stability, targeting, drug loading, and importantly, ensure that synergistic drugs work at one destination. This study uses 10-hydroxycamptothecin (HCPT) to construct a polymeric prodrug micelle, and the demethylcantharidin (DMC) is proportionally encapsulated within the micelle. Triggered by reactive oxygen species (ROS), HCPT and DMC were released simultaneously from the co-delivery platform in tumor cells. DMC promotes abnormal cell division by inhibiting the synthesis of the cell cycle checkpoint kinase Protein phosphatase 2A (PP2A), leading to increased cell vulnerability to DNA damage, disordered replication, and death. The co-delivery platform exhibited satisfactory biosafety and antitumor efficacy in vivo. The proposed co-delivery platform may provide a valuable reference for the translation of clinical combination chemotherapy regimens into nano-drug delivery systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Potent tumor regression remains challenging due to the lack of effective targeted drug delivery into deep tumors as well as the reduced susceptibility of cancer cells to anticancer agents in hypoxic environments. Bacteria-driven drug-delivery systems are promising carriers in overcoming targeting and diffusion limits that are inaccessible for conventional antitumor drugs. In this study, probiotic facultative anaerobe Escherichia coli Nissle 1917 (EcN) was functionalized and formed self-propelled microrobots to actively deliver therapeutic drug and photosensitizer to the deep hypoxic regions of tumors. Doxorubicin (Dox) was firstly modified with cis-aconityl anhydride (CA) and terminal thiol-decorated hydrazone derivative (Hyd-SH) through dual pH-sensitive amide and imine bonds, respectively. The functionalized CA-Dox-Hyd-SH was further coordinated with photosensitizer gold nanorods (AuNRs) and then conjugated to the surface of EcN. The resulting microrobots (EcN-Dox-Au) inherited the mobility characteristics and bioactivity of native EcN. Upon the irradiation of NIR laser, the microrobots exhibited enhanced tumor accumulation and penetration into the deep hypoxia tumor site. Strikingly, after 21 days of treatment with EcN-Dox-Au formulations, complete tumor regression was achieved without relapse for at least 53 days. This self-propelled strategy utilizing bacteria-driven microrobots provides a promising paradigm for enhancing drug penetration and elevating chemosensitivity, resulting in a superior antitumor effect. STATEMENT OF SIGNIFICANCE: Self-propelled Escherichia coli Nissle 1917 (EcN) - mediated microrobots are functionalized to co-deliver therapeutic drugs and photosensitizers to the deep tumor site. Anti-tumor drug doxorubicin (Dox) was modified through dual pH-sensitive bonds on both terminals and then linked with EcN and photosensitizer gold nanorods (AuNRs) to realize tumor microenvironment acidic pH-responsive drug release. Upon irradiation with a NIR laser near the tumor site, AuNRs produced a photothermal effect which realized the superficial tumor thermal ablation and increased the permeability of the tumor cell membrane to facilitate the penetration of microrobots. Moreover, the deep penetration of microrobots also enhanced the susceptibility of the cancer cells to Dox, and realized the complete tumor regression in the established breast cancer-bearing mice without recurrence using a lower dose of drug regimen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In recent years, reactive oxygen species (ROS)-mediated cancer therapies have been widely recognized for their high selectivity and good biological safety. However, due to the difficulties of endogenous tumor microenvironment (TME), penetration of tumor tissues and integration of multimodal tumor ablation, the treatment with traditional therapies could not achieve satisfactory tumor inhibition effects. Here, a doxorubicin (DOX)-glucose oxidase (GOx) dual-loaded and poly (2-ethyl-2-oxazoline) (PEOz) decorated magnetic polydopamine nanoparticles (Fe 3 O 4 -DOX@PDA-GOx@PEOz, FDPGP) were constructed for tumor ablation. GOx-mediated cascade enzyme reactions could amplify oxidative stress damage and further synergistically inhibit breast cancer. Its pH-responsive charge reversal, drug-controlled release, photothermal, and cascade reactions were evaluated through extracellular experiments. Cellular uptake, cell cytotoxicity, tumor penetration and therapeutic efficacy of FDPGP were investigated through intracellular experiments. Finally, in vivo distribution, photothermal, synergistic antitumor therapeutic effect and biosafety were evaluated comprehensively by in vivo experiments. Excitingly, outstanding tumor enrichment and penetration, superior anticancer effects and biosafety were achieved by the combination of photothermal therapy (PTT)/starvation therapy (ST)/chemodynamic therapy (CDT)/chemotherapy (CT). As such, the FDPGP nanoplatform provides a new insight into the development of collaboratively multimodal enhanced tumor therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The application of nanoarchitectures in cancer therapy seems to be beneficial for the delivery of antitumor drugs. In recent years, attempts have been made to reverse drug resistance, one of the factors threatening the lives of cancer patients worldwide. Gold nanoparticles (GNPs) are metal nanostructures with a variety of advantageous properties, such as tunable size and shape, continuous release of chemicals, and simple surface modification. This review focuses on the application of GNPs for the delivery of chemotherapy agents in cancer therapy. Utilizing GNPs results in targeted delivery and increased intracellular accumulation. Besides, GNPs can provide a platform for the co-delivery of anticancer agents and genetic tools with chemotherapeutic compounds to exert a synergistic impact. Furthermore, GNPs can promote oxidative damage and apoptosis by triggering chemosensitivity. Due to their capacity for providing photothermal therapy, GNPs can enhance the cytotoxicity of chemotherapeutic agents against tumor cells. The pH-, redox-, and light-responsive GNPs are beneficial for drug release at the tumor site. For the selective targeting of cancer cells, surface modification of GNPs with ligands has been performed. In addition to improving cytotoxicity, GNPs can prevent the development of drug resistance in tumor cells by facilitating prolonged release and loading low concentrations of chemotherapeutics while maintaining their high antitumor activity. As described in this study, the clinical use of chemotherapeutic drug-loaded GNPs is contingent on enhancing their biocompatibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Melanoma, the deadliest skin cancer with high metastasis potential, has posed a great threat to human health. Accordingly, early efficient blocking of melanoma progression is vital in antitumor treatment. Herein, a reduction-responsive dextran-based Pt(IV) nano-prodrug (PDPN) was synthesized and used for doxorubicin (DOX) delivery to combat melanoma synergistically. First, PDPN was prepared by one-pot chemical coupling of carboxylated methoxy poly(ethylene glycol) (mPEG), dextran (Dex), and the crosslinking agent cisPt (IV)-COOH. PDPN had a spherical structure (R h  = 34 ± 11.3 nm). Then, DOX was encapsulated into the PDPN core to form DOX-loaded PDPN (PDPN-DOX). The obtained PDPN-DOX displayed reduction-responsive release of DOX and Pt, thus showing a synergistic anticancer effect in B16F10 cells (combination index, 0.46). Furthermore, in vivo experiments demonstrated that PDPN-DOX was effective for the synergistic treatment of subcutaneous melanoma. Collectively, the as-prepared PDPN could serve as a promising and versatile nano-prodrug carrier for the co-delivery of chemotherapeutics in tumor combination therapy., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A hollow mesoporous manganese dioxide-based (H-MnO 2 ) multifunctional nanoplatform, H-MnO 2 @AFIPB@PDA@Ru-NO@FA (MAPRF NPs), was prepared for synergistic cancer treatment, in which a histone deacetylase inhibitor AFIPB was loaded in its hollow cavity and a ruthenium nitrosyl donor (Ru-NO) and a folic acid (FA) targeting group were covalently decorated on its covered polydopamine (PDA) layer. The MAPRF NPs showed tumor microenvironment (TME)-responsive properties of depletion of glutathione (GSH) to disrupt the antioxidant defense system and on-demand drug delivery. And the released Mn 2+ further catalyzed the decomposition of endogenous H 2 O 2 to produce highly toxic hydroxyl radicals (·OH) for enhanced chemodynamic therapy (CDT). Furthermore, upon 808 nm light irradiation MAPRF NPs exhibited controlled nitric oxide (NO) delivery and simultaneously produced significant photothermal effect. Consequently, MAPRF NPs showed high mortality toward cancer cells in the presence of 808 nm light irradiation. This work provides a paradigm of multimodal synergistic therapy that combines NO-based gas therapy with TME modulation for efficient antitumor therapy., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The synergistic effect of chemotherapy and photo-dynamic therapy (PDT) is an effective way to improve the efficiency of tumor treatment. However, most synergistic therapeutic drugs have poor water solubility and stability, so it is difficult to achieve high therapeutic effects while avoiding the severe side effects. Herein, a unique dandelion-like nanomedicine (named as cRGDfk-CCPT-mCe6) was successfully synthesized using Ce6-loaded amphiphilic β-cyclodextrins (β-CD) doped lipid-based vesicles as the core (receptacle) and β-CD modified camptothecin (CPT) pro-drug as the flyable dandelion seeds. The β-CD modified CPT pro-drug was introduced into the core vesicles in succession via host-guest interaction between inter-molecular β-CD and CPT, and cRGDfk peptides were further introduced as the outermost layer (stigma) to enhance the internalization into cancer cells. CPT interacted with β-CD through glutathione (GSH)-cleavable disulfide bonds, which led to drug release in glutathione-rich cancer cells, just as spread of dandelion seeds in the wind. GSH consumption further disrupted the intracellular redox homeostasis of cancer cells through combined action of Ce6 with light irradiation and the synergistic anti-tumor effect was thus achieved, resulting in apoptosis of cancer cells. Therefore, the nanomedicine provides a facile and versatile anti-tumor strategy, as well as a persistent anti-cancer effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) has many exceptional advantages in cancer treatment, such as minor trauma, low toxicity side effects, and strong adaptability, effectively overcoming some obstacles of traditional therapy and providing more revolutionary opportunities for curing cancer. Chlorin e6 (Ce6) exhibits excellent singlet oxygen generation and conversion efficiency under near-infrared laser irradiation and is a promising PDT photosensitizer. However, its hydrophobicity, short half-life and lack of tumor specificity limit its in vivo anticancer application. Therefore, this work has designed and prepared a multifunctional nanoplatform, Ce6/FeOOH@BSA, to efficiently deliver Ce6. Nanoparticles exhibit excellent dispersion and stability in deionized water, PBS and DMEM, and the blood half-life is 3.98 ± 0.31 h. The nanoplatform demonstrates effective tumor targeting and accumulation, overcoming the obstacles of the biological application of Ce6. Iron ions can exert a chemodynamic therapy (CDT) effect by reacting with overexpressed H 2 O 2 in the tumor to generate toxic hydroxyl radicals (·OH). Moreover, FeOOH nanoparticles effectively promote glutathione (GSH) consumption in tumor cells, which is conducive to accumulating reactive oxygen species (ROS). In brief, Ce6/FeOOH@BSA nanoparticles realize the targeted delivery of Ce6 and mediate synergistic PDT/CDT against tumors, broadening the biomedical application of nanomaterials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The low permeability of antifungal agents to fungal biofilms, which allows the continued survival of the fungus inside, is a key issue that makes fungal infections difficult to cure. Inspired by the unique dynamic molecule motion properties of the polyrotaxane (PR) nanomedicine, herein, a dynamic delivery system Clo@mPRP/NONOate was fabricated by co-loading nitric oxide (NO) and the antifungal drug clotrimazole (Clo) onto the α-cyclodextrin (α-CD) PR modified mesoporous polydopamine (mPDA) nanoparticles, in which pentaethylenehexamine (PEHA) was grafted to α-CDs. The cationic α-CDs endowed this dynamic NO/Clo codelivery system with the ability to effectively attach to fungal biofilms through electrostatic interaction, while the introduction of PRs with flexible molecule motion (slide and rotation of CDs) enhanced the permeability of nanoparticles to biofilms. Meanwhile, NO could effectively inhibit the formation of fungal hyphae, showing an dissipating effect on mature biofilms, and could be further combined with Clo to completely eradicate fungi inside the biofilms. In addition, the dynamic system Clo@mPRP/NONOate could efficiently and synergistically eliminate planktonic Candida albicans (C. albicans) in a safe and no toxic side effect manner, and effectively cured C. albicans-induced vaginal infection in mice. Therefore, this dynamic NO/Clo codelivery system provided an effective solution to the clinical treatment of C. albicans-induced vaginal infection, and the application prospect could even be extended to other microbial infectious diseases. STATEMENT OF SIGNIFICANCE: A dynamic codelivery system based on cationized cyclodextrin polyrotaxane combining nitric oxide and antifungal drugs clotrimazole was prepared to deal with the issue of clinical fungal biofilm infection. This dynamic codelivery system could be attached to the Candida albicans biofilms and penetrate into biofilm via flexible molecular mobility to effectively eradicate the fungi. This dynamic codelivery system could synergistically and efficiently eliminate planktonic-state Candida albicans, but did not show significant cytotoxicity to normal somatic cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nanomaterials in particular the magnetic nanoparticles (MNPs) offer tremendous potential for cancer treatment due to their unique intrinsic properties. Combining materials with a variety of functional groups, and forming a multifunctional nanosystem to overcome the limitations of monotherapy for cancer treatment has always been a research focus with notable difficulties. Considering the many challenges faced by radiotherapy and hyperthermia, in this study, we designed a rational strategy for magnetic hyperthermia using Fe 3 O 4 @SiO 2 @Sec2@FA nanoparticles as a novel nano-radiosensitizer to simultaneously enhance the therapeutic effects of radiotherapy in the future. Fe 3 O 4 @SiO 2 core-shell structured nanoparticles were synthesized with an appropriate silica layer thickness to maintain good saturation magnetization. The as-prepared Fe 3 O 4 @SiO 2 @Sec2@FA nanoparticles had the specific absorption rate (SAR)value of 57 W/g, which was below the clinically acceptable alternating magnetic field value of 4.9 × 10 9 Am -1 s -1 , indicating good heat generation efficiency (the temperature level ΔT=6-10 °C). Moreover, Folate-modified nanoparticles exhibited approximately 6-fold higher cellular internalization of Hela cells with no obvious cytotoxicity for the Hela and MDA-MB-231 cells, and lower cytotoxicity for the HUVECs in a concentration range of 0-150 µg/mL. In addition, these nanoparticles were modified on the silica surface by L-selenocystine, which could enhance the elimination of tumor cells by producing reactive oxygen species under X-rays, resulting in a novel radiosensitization effect. Therefore, the as-prepared Fe 3 O 4 @SiO 2 @Sec2@FA nanoparticles with good biocompatibility and active targeting would possess synergistic magnetic hyperthermia/radiotherapy effect., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso‑tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm 2 ), ROS generated from laser-excited TCPP in TCPP@SeSe-CPT nanomicelles could break the diselenium bonds to achieve the light-controlled release of CPT. In addition, the photosensitizer TCPP could also be imaged at the tumor site. Due to the photodynamic therapy from laser-excited TCPP and chemotherapy from photocontrolled release of CPT in TCPP@SeSe-CPT, our designed nanomicelles yielded potent antitumor effects both in vitro and in vivo., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Poor tumor specificity is one of the key obstacles for clinical applications of nanotheranostic agents, consequently leading to serious side effects and unsatisfactory therapeutic efficacy. Herein, biomolecule-based nanohybrids (named as Hb-PDA-GOx) with multiple stimuli-responsiveness were designed and fabricated to enhance tumor-specific therapy. The nanohybrids embodied two proteins, i.e., hemoglobin (Hb) and glucose oxidase (GOx), which exhibited cascade catalytic activity selectively within the tumor microenvironment (TME). Specifically, GOx catalyzes the overexpressed glucose into gluconic acid and hydrogen peroxide (H 2 O 2 ), which not only initiated starvation therapy (ST) through cutting off the nutrition supply for carcinoma cells, but also provided H 2 O 2 for sequential Fenton reaction induced by Hb that generating biotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). Moreover, localized heat generation from polydopamine (PDA) in the nanohybrids can implement photothermal therapy (PTT) and reinforce the CDT efficacy. Excitingly, effective eradication of solid tumors and significant suppression of metastatic tumors growth were achieved by utilizing Hb-PDA-GOx as a versatile theranostic agent. All these results had been verified by in vitro and/or in vivo experiments. In light of the superior anticancer effects and insignificant systemic toxicity, the as-fabricated biomolecule-based nanohybrids could be employed as a promising agent for tumor-specific therapy. More importantly, the high biocompatibility and biodegradability of the selected biomolecules would facilitate subsequent clinical translation. STATEMENT OF SIGNIFICANCE: (1) A facile one-pot synthesis strategy was proposed to fabricate biomolecule-based tumor theranostic agent with high biocompatibility and biodegradability, which would facilitate subsequent clinical translation; (2) The as-developed theranostic agent was endowed with multiple stimuli-responsiveness for achieving tumor-specific and cascade-enhanced synergistic therapy; (3) The in vivo experiments demonstrated that the as-developed theranostic agent can not only effectively eradicate solid tumors, but also significantly suppress metastatic tumors growth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Bacterial biofilm is notorious for causing chronic infections, whose antibiotic treatment is bringing about severe multidrug resistance and environmental contamination. Stimuli-responsive nanocarriers have become encouraging materials to combat biofilm infections with high efficiency and low side effect. Herein, a charge-switchable and pH-responsive nanocomplex is fabricated via a facile aqueous one-pot zeolitic imidazolate framework-8 (ZIF-8) encapsulation of proteinase K (PK) and photosensitizer Rose Bengal (RB), for enzymatic and photodynamic therapies (PDT) against biofilm infections. Once encountering in acidic microenvironment, the surface charge of nanocomplex can switch self-adaptively from negative to positive, hence remarkably facilitating the biofilm penetration of nanocomplex. After acid-induced decomposition of nanocomplex, the released PK degrades biofilm matrix and loosens its structure, promoting diffusion of RB inside the biofilm. Afterwards, upon visible light illumination, the RB generates highly reactive oxygen species (ROS), which can readily and efficiently kill the remained bacteria even in the biofilm core. The charge-assisted penetration makes PK and RB fully functional, resulting in a cooperative effect concerning high biofilm eradication capacity, as testified by biofilm models both in vitro and in vivo. The green synthesis and good therapeutic performance of the nanocomplex manifests its considerable potential as a nontoxic and effective platform for biofilm treatment., Competing Interests: Declaration of Competing Interest The authors declare no interest conflict., (Copyright © 2022. Published by Elsevier B.V.)

Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation, high drug-loading efficiency, and excellent therapeutic efficacy. Herein, MnAs-ICG nanospike was generated by self-assembly of indocyanine green (ICG), manganese ions (Mn 2+ ), and arsenate (AsO 4 ) based on electrostatic and coordination interactions, effectively integrating the bimodal imaging ability of magnetic resonance imaging (MRI) and fluorescence (FL) imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an "all-in-one" theranostic nano-platform. The as-prepared MnAs-ICG nanospike had a uniform size, well-defined nanospike morphology, and impressive loading capacities. The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability, enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components. 3- ) based on electrostatic and coordination interactions, effectively integrating the bimodal imaging ability of magnetic resonance imaging (MRI) and fluorescence (FL) imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an "all-in-one" theranostic nano-platform. The as-prepared MnAs-ICG nanospike had a uniform size, well-defined nanospike morphology, and impressive loading capacities. The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability, enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components. In vitro results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect, prolonged blood circulation and increased tumor accumulation compared to their individual components, effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect. Taken together, this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect, prolonged blood circulation and increased tumor accumulation compared to their individual components, effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect. Taken together, this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The reduction of reactive oxygen species (ROS) and inflammatory factor levels plays an important role in the treatment of colitis. A series of ROS-responsive lipids (ZnDPA-R) based on the thioketal structure were designed and synthesized. It was expected that the lipidic materials could combine ROS consumption and siRNA delivery capacity to achieve synergistic treatment of colitis. The target liposomes could combine with the phosphate backbone of siRNA to form lipoplexes of size ∼100 nm and could deliver siRNA cargo into the cell. The results of in vitro anti-inflammatory experiments showed that the lipids may effectively consume ROS in the cells. The lipoplexes significantly reduced the expression levels of TNF-α mRNA and related inflammatory factors in macrophages. After PEGylation, the lipoplex was used for treating mouse colitis, and the biodistribution results proved that the lipoplexes effectively aggregated in the intestine. The delivery system could not only respond to the high ROS level in colitis through breaking of thioketal structure, but it could also assist in treating inflammation by ROS consumption. The treatment results revealed that the levels of TNF-α mRNA and related inflammatory factors in the colon lesion were largely reduced, and the inflammatory symptoms were significantly relieved. Hematology test results indicated that the treatment was safe and induced no side effects in mice. The present study may shed light on the synergistic treatment of colitis through anti-inflammatory siRNA delivery and ROS depletion strategies. STATEMENT OF SIGNIFICANCE: Downregulation of inflammatory factors and reactive oxygen species (ROS) levels is critical in treating colitis. In the present study, a series of ROS-responsive lipid molecules based on the Zn-DPA headgroup and thioketal linkage were synthesized for delivering TNF-α siRNA and for treating colitis. In addition to silencing the expression of TNF-α mRNA and the related inflammatory factors, the material also achieved synergistic treatment by simultaneous consumption of ROS in the colon lesion. In vitro cell experiments and in vivo colitis treatment in mice showed that the lipoplex exerted a satisfactory therapeutic effect on colitis, and the symptoms of colitis in mice were significantly alleviated. The present study may shed light on the synergistic treatment for colitis through anti-inflammatory siRNA delivery and ROS depletion strategies., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)