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Despite the tremendous potential of DNAzymes in gene therapy, achieving gene regulation with spatiotemporal precision and satisfactory efficacy remains a key challenge. Herein, we developed a near‐infrared light (NIR)‐triggered cascade effect system that enables precise spatiotemporal gene silencing and gas‐synergistic cancer therapy. This nanoplatform was constructed using an enzyme‐activatable DNAzyme, a nitric oxide (NO) precursor, and upconversion nanoparticles (UCNPs). The UCNPs act as light converters, facilitating the precursor to produce NO under NIR light irradiation, while the generated NO not only participates directly in gas therapy but also induces the upregulation of cytoplasmic APE1 level, resulting in enhanced DNAzyme activation and spatially controlled gene silencing. By leveraging this mechanism, cascade effects mediated gas‐gene synergistic therapy is achieved through the combination of NIR light‐controlled NO release and APE1‐activatable gene therapy. We demonstrated that this nanoplatform enables enhanced anti‐tumor effects both in vitro and in vivo. This strategy represents a critical step forward in the quest for highly targeted and efficient cancer treatments. [ABSTRACT FROM AUTHOR]

Yong-Gyu Jeong,1 Joo-Hwan Park,2 Dongwoo Khang1,3,4 1Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea; 2Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, 21565, South Korea; 3Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea; 4Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South KoreaCorrespondence: Dongwoo Khang, Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South Korea, Tel +82 32 899 1525, Email dkhang@gachon.ac.kr Joo-Hwan Park, Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University, Incheon, 21565, South Korea, Tel +82-32-460-3229, Email replica1874@gilhospital.comAbstract: The advent of acoustically responsive nanodrugs that are specifically optimized for sonodynamic therapy (SDT) is a novel approach for clinical applications. Examining the therapeutic applications of sono-responsive drug delivery systems, understanding their dynamic response to acoustic stimuli, and their crucial role in enhancing targeted drug delivery are intriguing issues for current cancer treatment. Specifically, the suggested review covers SDT, a modality that enhances the cytotoxic activity of specific compounds (sonosensitizers) using ultrasound (US). Notably, SDT offers significant advantages in cancer treatment by utilizing US energy to precisely target and activate sonosensitizers toward deep-seated malignant sites. The potential mechanisms underlying SDT involve the generation of radicals from sonosensitizers, physical disruption of cell membranes, and enhanced drug transport into cells via US-assisted sonoporation. In particular, SDT is emerging as a promising modality for noninvasive, site-directed elimination of solid tumors. Given the complexity and diversity of tumors, many studies have explored the integration of SDT with other treatments to enhance the overall efficacy. This trend has paved the way for SDT-based multimodal synergistic cancer therapies, including sonophototherapy, sonoimmunotherapy, and sonochemotherapy. Representative studies of these multimodal approaches are comprehensively presented, with a detailed discussion of their underlying mechanisms. Additionally, the application of audible sound waves in biological systems is explored, highlighting their potential to influence cellular processes and enhance therapeutic outcomes. Audible sound waves can modulate enzyme activities and affect cell behavior, providing novel avenues for the use of sound-based techniques in medical applications. This review highlights the current challenges and prospects in the development of SDT-based nanomedicines in this rapidly evolving research field. The anticipated growth of this SDT-based therapeutic approach promises to significantly improve the precision of cancer treatment. Keywords: sonodynamic therapy, ultrasound, synergistic therapy, sonosensitizer, nanomedicine, cancer treatment, acoustic audible wave

Nanocatalytic therapeutic agents with triple synergistic treatment modes of chemodynamic therapy (CDT), photothermal therapy (PTT) and photodynamic therapy (PDT) are emerging nanomaterials in malignancy treatment. Nevertheless, the passive diffusion and transport of nanomaterials result in poor permeability in tumor lesions, severely affecting the effectiveness of synergistic therapy. Herein, a dual‐source‐driven parachute‐like Au2Pt@PMO@ICG Janus nanomotor (APIJNS) is prepared by an interfacial energy‐mediated anisotropic growth strategy for PTT‐mediated CDT/PDT triple synergistic cancer therapy. Such nanomotor can realize self‐thermophoresis drive under the trigger of near‐infrared light, which can effectively enhance the active permeability and uptake of the APIJNS in the tumor tissue, thus achieving efficient PTT/PDT/CDT synergistic therapeutic effect. In addition, parachute‐like APIJNS exhibits high‐efficiency catalase (CAT)‐like activity and can catalyze the overexpressed H2O2 in the tumor microenvironment (TME) to generate oxygen (O2), not only alleviating the hypoxia in the tumor lesion, but also converting it into singlet oxygen (1O2) to activate the photosensitizer ICG, achieving PDT. This work provides new ideas for enhancing triple synergistic cancer therapy by improving tumor permeability with dual‐drive Janus nanomotors based on dual noble metal nanozymes. [ABSTRACT FROM AUTHOR]

Photothermal, photodynamic and sonodynamic cancer therapies offer opportunities for precise tumor ablation and reduce side effects. The cyclic guanylate adenylate synthase-stimulator of interferon genes (cGAS-STING) pathway has been considered a potential target to stimulate the immune system in patients and achieve a sustained immune response. Combining photothermal, photodynamic and sonodynamic therapies with cGAS-STING agonists represents a newly developed cancer treatment demonstrating noticeable innovation in its impact on the immune system. Recent reviews have concentrated on diverse materials and their function in cancer therapy. In this review, we focus on the molecular mechanism of photothermal, photodynamic and sonodynamic cancer therapies and the connected role of cGAS-STING agonists in treating cancer. [ABSTRACT FROM AUTHOR]

Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis. [ABSTRACT FROM AUTHOR]

The research trend of cancer treatment has shifted from monotherapy to combination therapy. In this study, mesoporous bioactive glass (MBG) was used as a drug carrier, that combined photothermal therapy (PTT) and photodynamic therapy (PDT). The condition for photothermal therapy to achieve effective treatment is local hyperthermia in a short time, to achieve that, this study chose bismuth nanoparticle, an element that has good biocompatibility and high photothermal conversion efficiency (PCE = ∼40 %) under the irradiation of near-infrared (NIR) laser, as photothermal agent. A photosensitizer-indocyanine green (ICG), which has good biocompatibility and can be triggered with NIR to generate reactive oxygen species (ROS), was also loaded in MBG. The MBG loaded with a photothermal agent and photosensitizer was named MBG@Bi-ICG. MBG@Bi has an excellent PCE = 47.67 %, which helps to reach enough temperature for therapeutic effect. In combination with ICG, MBG@Bi-ICG achieves great cytotoxicity against A549 cancer cells after the irradiation of 808 nm laser source (IC50 = 96.5 μg/mL), due to the synergistic effect of local hyperthermia generated by the photothermal agent-bismuth nanoparticle, and ROS generated by photosensitizer-ICG. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is one of the most prevalent cancers, primarily affecting women. Among its subtypes, estrogen receptor-positive (ER+) breast cancer is particularly common. Inhibiting estrogen's effects is crucial for treating ER+ breast cancer, but current therapies often have significant side effects and limitations. Chrysin, a natural flavonoid, has shown potential in reducing estrogen receptor expression, but its poor water solubility hampers clinical application. This study explores the use of mesoporous dopamine nanoparticles (mPDA) to enhance the delivery and efficacy of Chrysin, combined with photothermal therapy (PTT), for breast cancer treatment. Methods: Chrysin-loaded mPDA nanoparticles (Chrysin@mPDA) were synthesized and characterized for their morphology, drug-loading efficiency, stability, and photothermal properties. Network pharmacology was used to predict Chrysin's mechanisms in breast cancer, which were validated through gene expression analysis in cell experiments. The therapeutic efficacy of Chrysin@mPDA with and without PTT was evaluated in a mouse model of breast cancer, with tumor volume and weight measured. Immunohistochemical analysis was conducted to assess estrogen receptor expression and immune cell infiltration in tumor tissues. Results: Chrysin@mPDA nanoparticles demonstrated a high drug-loading capacity and excellent stability. Photothermal studies confirmed the nanoparticles' ability to generate heat upon laser exposure, significantly enhancing Chrysin release in acidic conditions with laser irradiation. Network pharmacology identified key target genes affected by Chrysin, including ESR1, BRCA1, CTNNB1, and BAX, which were validated through qPCR. In vivo, the combination of Chrysin@mPDA and PTT significantly reduced tumor volume and weight, decreased estrogen receptor-positive cells, and increased infiltration of CD3+CD4+ and CD3+CD8+ T cells in tumor tissues. Discussion: The study highlights the potential of Chrysin-loaded mPDA nanoparticles combined with PTT as an effective strategy for breast cancer treatment. This approach addresses the limitations of Chrysin's solubility and enhances its therapeutic efficacy through synergistic mechanisms. The dual action of Chrysin in modulating gene expression and PTT in inducing localized hyperthermia and immune response suggests a promising avenue for improved breast cancer prognosis and reduced recurrence. [ABSTRACT FROM AUTHOR]

Migration is an initial step in tumor expansion and metastasis; suppressing cellular migration is beneficial to cancer therapy. Herein, we designed a novel biogated nanoagents that integrated the migration inhibitory factor into the mesoporous silica nanoparticle (MSN) drug delivery nanosystem to realize cell migratory inhibition and synergistic treatment. Antisense oligonucleotides (Anti) of microRNA-330-3p, which is positively related with cancer cell proliferation, migration, invasion, and angiogenesis, not only acted as the locker for blocking drugs but also acted as the inhibitory factor for suppressing migration via gene therapy. Synergistic with gene therapy, the biogated nanoagents (termed as MSNs-Gef-Anti) could achieve on-demand drug release based on the intracellular stimulus-recognition and effectively kill tumor cells. Experimental results synchronously demonstrated that the migration suppression ability of MSNs-Gef-Anti nanoagents (nearly 30%) significantly contributed to cancer therapy, and the lethality rate of the non-small-cell lung cancer was up to 70%. This strategy opens avenues for realizing efficacious cancer therapy and should provide an innovative way for pursuing the rational design of advanced nano-therapeutic platforms with the combination of cancer cell migratory inhibition. [ABSTRACT FROM AUTHOR]

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)‐based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade‐off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone‐lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs‐based two‐component nanoplatform consisting of prodrug‐loaded AuNPs‐ImLND and tumor‐targeting peptide RGD‐conjugated AuNPs‐DBCO‐RGD is designed. In the therapeutic regimen, AuNPs‐DBCO‐RGD are intravenously injected first for tumor‐specific enrichment and retention. Once the arrival of AuNPs‐ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT. [ABSTRACT FROM AUTHOR]

Introduction: The synergistic treatment of chemotherapy and photodynamic therapy (PDT) has remarkable potential in cancer therapy. However, challenges remain, such as unstable chemotherapeutic drug release, suboptimal targeting, and reduced efficacy of PDT under hypoxic conditions commonly found in solid tumors. Methods: To address these issues, we use camptothecin (CPT) and pheophorbide a (Pa) incorporated through the functional thioketal, which serves as the reactive oxygen species (ROS)-responsive trigger, to construct a ROS-responsive prodrug (CPT-TK-Pa). Subsequently, we co-loaded it with a platinum nanozyme (PtNP) in distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to obtain the ROS-responsive prodrug nanoparticle (CPT-TK-Pa/Pt NP). Results and Discussion: Specifically, the incorporated PtNP within CPT-TK-Pa/Pt NPpositively catalyzes the conversion of hydrogen peroxide (H2O2) tooxygen, thereby ameliorating the hypoxic state of the tumor. This enhanced oxygen generation could replenish the oxygen that is consumed by Pa during 660 nm exposure, enabling controlled CPT release and amplifying the photodynamic response. In vitro investigations reveal the potency of CPT-TK-Pa/Pt NPs in inhibiting colon tumor cells. Given its ROS-responsive releasemechanismand enhanced PDT efficacy, CPTTK-Pa/Pt NP has the potential to be a promising candidate for cancer therapy. [ABSTRACT FROM AUTHOR]

The photothermal performance of black phosphorus (BP) in the near infrared (NIR)‐II bio‐window (1000–1500 nm) is low, which limits its biomedical applications. Herein, ultrasmall nickel phosphide quantum dots (Ni2P QDs) are synthesized with BP quantum dots (BPQDs) as the template by topochemical transformation. The size of Ni2P QDs is ≈3.5 nm, similar to that of BPQDs, whereas the absorption and photothermal conversion efficiency of Ni2P QDs at 1064 nm (43.5%) are significantly improved compared with those of BPQDs. To facilitate in vivo applications, an Ni2P QDs‐based liposomal nano‐platform (Ni2P‐DOX@Lipo‐cRGD) is designed by incorporation of Ni2P QDs and doxorubicin (DOX) into liposomal bilayers and the interior, respectively. The encapsulated DOX is responsively released from liposomes upon 1064‐nm laser irradiation owing to the photothermal effect of Ni2P QDs, and the drug release rate and amount are controlled by the light intensity and exposure time. In vivo, experiments show that Ni2P‐DOX@Lipo‐cRGD has excellent tumor target capability and biocompatibility, as well as complete tumor ablation through the combination of photothermal therapy and chemotherapy. The work provides a new paradigm for the NIR‐II transformation of nano‐materials and may shed light on the construction of multifunctional nano‐platforms for cancer treatment. [ABSTRACT FROM AUTHOR]

Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B‐responsive polymeric nanoparticle prodrug system is employed for co‐delivery of PTX and CAP, resulting in a polymeric nano‐drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3‐kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co‐delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC. [ABSTRACT FROM AUTHOR]

[Display omitted] Reprogramming immunosuppressive M2 macrophages into M1 macrophages in tumor site provides a new strategy for the immunotherapy of colorectal cancer. In this study, M1 macrophage-derived exosome nanoprobe (M1UC) with Ce6-loaded upconversion material is designed to enhance the photodynamic performance of Ce6 while reprogramming M2 macrophages at tumor site and producing NO gas for three-mode synergistic therapy. Under the excitation of near-infrared light at 808 nm, the probe can generate 660 nm up-conversion fluorescence, which enables the photosensitizer Ce6 to produce ROS efficiently. In addition, the probe leads the production of NO by nitric oxide synthase on exosomes. Confocal laser and flow cytometry results show that M1UC probe reprograms M2 macrophages into M1 macrophages with an efficiency of 95.12%. The cell experiments show that the apoptosis rate of the three-mode synergistic therapy group is 78.8%, and the therapeutic effect is significantly higher than those of the other single treatment groups. In vivo experiments results show that M1UC probes maximally gather at the tumor site after 12 h of intravenous injection in orthotopic colorectal cancer mice. After 808 nm laser irradiation, the survival rate of mice is 100% and the recurrence rate was 0 within 60 d, and the therapeutic effect is significantly higher than those of other single treatment groups, which is also confirmed by immunohistochemistry. This M1 macrophage-derived exosome nanoplatform which is based on the three modes of immunotherapy, gas therapy and photodynamic therapy, provides a new design idea for the diagnosis and treatment of deep tumors. [ABSTRACT FROM AUTHOR]

The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis‐resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self‐powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Tumor microenvironment (TME) stimuli-responsive nanoassemblies are emerging as promising drug delivery systems (DDSs), which acquire controlled release by structural transformation under exogenous stimulation. However, the design of smart stimuli-responsive nanoplatforms integrated with nanomaterials to achieve complete tumor ablation remains challenging. Therefore, it is of utmost importance to develop TME-based stimuli-responsive DDSs to enhance drug-targeted delivery and release at tumor sites. Herein, we proposed an appealing strategy to construct fluorescence-mediated TME stimulus-responsive nanoplatforms for synergistic cancer therapy by assembling photosensitizers (PSs) carbon dots (CDs), chemotherapeutic agent ursolic acid (UA), and copper ions (Cu2+). First, UA nanoparticles (UA NPs) were prepared by self-assembly of UA, then UA NPs were assembled with CDs via hydrogen bonding force to obtain UC NPs. After combining with Cu2+, the resulting particles (named UCCu2+ NPs) exhibited quenched fluorescence and photosensitization due to the aggregation of UC NPs. Upon entering the tumor tissue, the photodynamic therapy (PDT) and the fluorescence function of UCCu2+ were recovered in response to TME stimulation. The introduction of Cu2+ triggered the charge reversal of UCCu2+ NPs, thereby promoting lysosomal escape. Furthermore, Cu2+ resulted in additional chemodynamic therapy (CDT) capacity by reacting with hydrogen peroxide (H 2 O 2) as well as by consuming glutathione (GSH) in cancer cells through a redox reaction, hence magnifying intracellular oxidative stress and enhancing the therapeutic efficacy due to reactive oxygen species (ROS) therapy. In summary, UCCu2+ NPs provided an unprecedented novel approach for improving the therapeutic efficacy through the three-pronged (chemotherapy, phototherapy, and heat-reinforced CDT) attacks to achieve synergistic therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] Therapeutic modalities and drug formulations play a crucial and prominent role in actualizing effective treatment and radical cures of tumors. However, the therapeutic efficiency was severely limited by tumor recurrence and complex multi-step preparation of formulation. Therefore, the exploration of novel nanoparticles via a simple and green synthesis process for conquering traditional obstacles and improving therapeutic efficiency is an appealing, yet remarkably challenging task. Herein, a universal nanoplatform allows all cancerous cell-targeting, acid-responsive, cell imaging, synergistic chemotherapy, and nucleolar targeted phototherapy function was tactfully designed and constructed by using chemotherapeutic agents ursolic acid (UA), sorafenib (SF), and carbon dots (CDs) photosensitizers (PSs). The designed US NPs were formed by self-assembly of UA and SF associated with electrostatic, π-π stacking, and hydrophobic interactions. After hydrogen bonding reaction with CDs, the obtained (denoted as USC NPs) have a relatively uniform size of an average 125.6 nm, which facilitated the favorable accumulation of drugs at the tumor region through a potential enhanced permeability and retention (EPR) effect as compared to their counterpart of free CDs solution. Both in vitro and in vivo studies revealed that the advanced platform commenced synergistic anticancer therapeutic potency, imperceptible systematical toxicity, and remarkable reticence towards drug-resistant cancer cells. Moreover, the CDs PSs possess intrinsic nucleolus-targeting ability. Taken together, this theranostics system can fully play the role of "killing three birds with one stone" in a safe manner, implying a promising direction for exploring treatment strategies for cancer and endowing them with great potential for future translational research and providing a new vision for the advancing of an exceptionally forceful protocol for practical cancer therapy. [ABSTRACT FROM AUTHOR]

Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper‐induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN‐Cu/PEG/DSF) to realize on‐demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu2+ in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu+ species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN‐Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano‐therapeutic platforms. [ABSTRACT FROM AUTHOR]

The therapeutic application of chemodynamic therapy (CDT) is severely limited by the insufficient intracellular H 2 O 2 and acidity in tumor. Herein, an acid-sensitive nanoplatform (ZIF67-ICG/TAM@GOx) to promote H 2 O 2 and acidity enhancement through intracellular cyclic amplification for enhanced CDT is rationally designed. Notably, the acidic conditions of the tumor microenvironment (TME) can turn on the switch of the nanoplatform, setting free the loaded tamoxifen (TAM) and indocyanine green (ICG). The mitochondrial respiration inhibitor TAM and the superoxide dismutase-mimicking ZIF67 synergistically lead to an increase in the content of O 2 and H 2 O 2 , accelerating the depletion of β- d -glucose by GOx to generate gluconate and H 2 O 2. The gluconate in turn boosts the acidity to facilitate the collapse of nanoparticles, further significantly promoting the accumulation of intracellular H 2 O 2 through a positive circulation. Consequently, the amplificated endogenous H 2 O 2 is catalyzed by Co2+ to liberate hydroxyl radicals (•OH). Besides, ICG-mediated photothermal therapy (PTT) and GOx-induced starvation therapy along with CDT realize the synergistic cancer treatment. Importantly, in vitro and in vivo experiments verified that the nanoplatform performed superior specificity and excellent therapeutic responses. The smart nanoplatform overcomes H 2 O 2 and acidity deficiency simultaneously for intensive CDT, providing new prospects for the development of biocompatible cancer synergistic therapy strategies. In the tumor microenvironment, the released TAM, GOx and ZIF67 synergistically lead to a positive circulation for self-amplified CDT, cooperating with PTT and starvation to realize the synergistic cancer treatment. [Display omitted] • An acidic sensitive nanoplatform (ZIF67-ICG/TAM@GOx) is constructed for specific tumor therapy. • The combination of TAM, ZIF67 and GOx enabled positive circulation to accumulate H 2 O 2 and acidity for boosting CDT. • The disruption of H 2 O 2 homeostasis made the approach of "expanding source and cost-saving" for the increase of H 2 O 2. • The self-amplified CDT along with PTT, GOx-induced starvation realized a novel synergistic cancer therapy strategy. [ABSTRACT FROM AUTHOR]

Due to the limited penetration depth of visible light and insufficient oxygen supply in hypoxic tumor tissues, the development of near‐infrared (NIR) triggered and oxygen‐independent photodynamic therapy (PDT) to generate active radicals is necessary for cancer treatment. Herein, we developed a NIR‐triggered photothermal therapy (PTT) and oxygen‐independent PDT system based on metal‐organic frameworks (MOFs), which integrated indocyanine green (ICG) and 2,2'‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH) as NIR‐triggered photothermal units and temperature‐sensitive free radical initiator into ZIF‐8, respectively. AIPH was introduced into ZIF‐8 via a one‐pot strategy with high loading capacity (125 mg g−1). Through the irradiation of 808 nm laser, the ICG units could efficiently absorb NIR light to rapidly raise the local temperature to 44 °C within 3 minutes. Meanwhile, the local high temperature further induced the AIPH to continuously generate toxic alkyl radicals (R−C⋅). The combination of PTT and free radical therapy is significantly better than the single treatment mode. More importantly, the NIR‐triggered synergistic therapy could induce extensive apoptosis of cancer cells in hypoxic conditions, which sheds new light on the development of MOFs‐based photochemical therapy platform in the actual tumor microenvironment. [ABSTRACT FROM AUTHOR]

Due to its excellent photothermal performance, MoS 2 is more and more widely used in cancer treatment. In this study, a novel MoS 2 composite nanosheets material with lamellar structure and good water solubility (BBPL-MoS 2 -LP) was synthesized, which had high photothermal conversion efficiency and good biocompatibility. The drug loading efficiency of doxorubicin (DOX) on the composite nanosheets reached 34.43%. Compared with the drug release rate of 15% at pH 7.0, the release degree of DOX was higher at a slightly acidic environment of pH 5.5, reaching 30%. Under the irradiation of near infrared laser (NIR), the drug release was significantly enhanced, indicating that the composite material can be used as a dual response system. The release of DOX would be controlled by pH and near infrared laser (NIR) irradiation. It was also found that BBPL-MoS 2 -LP could effectively penetrate cell membrane under the endocytosis mechanism mediated by biotin receptor and release drugs in HeLa cells. Cytotoxicity and apoptosis experiments showed that BBPL-MoS 2 -LP had better ability to kill HeLa cells than single drug or photothermal irradiation alone. The as-prepared multifunctional composite nanosheets in this study has great potential in effective drug delivery and photothermal chemotherapy for tumor treatment. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

• The diabetic tumor microenvironment was found with high glucose and HSP90 levels. • The nanoenzyme was fueled by a high-glucose microenvironment. • The nanoenzyme decreased the expression of HSP90 in tumor cells. • The nanoenzyme enhanced the CDT and mild-temperature PTT effects. Diabetes is recognized as an independent risk factor for the onset and advancement of cancer. However, there has been limited emphasis on investigating the diabetic tumor microenvironment (TME) and harnessing its inherent microenvironmental distinctions to facilitate tumor ablation. The management of cancer with diabetes is often challenging. Herein, an activatable hollow mesoporous manganese silicate (H-Mn)/indocyanine green (ICG)/glucose oxidase (GOX) nanoenzyme (H-MIG) was developed for diabetic tumor therapy. This micro-reactor consumes glucose to trigger a sequential cascade reaction to biologically amplify the antitumor effect under hyperglycemia conditions. H-Mn degrades within the TME, releasing O 2 and Mn2+. The presence of O 2 promotes GOX-induced glucose consumption, leading to the subsequent production of H 2 O 2. This glucose-fueled oxidation also provides reactants for chemodynamic therapy, as H 2 O 2 and Mn2+ in the TME subsequently undergo a Fenton-like reaction. In addition, by inhibiting the expression of the heat shock protein 90, which is highly expressed in diabetic TME, GOX enhances ICG-guided mild-temperature photothermal therapy. In vitro and in vivo experiments demonstrated that the domino effect fueled by this high-glucose TME improves anticancer efficacy. By exploiting the complementary cascade reactions, this endogenous enzyme-based strategy could inspire the design of more promising advanced platforms for more efficient diabetic cancer therapy. [ABSTRACT FROM AUTHOR]

Stimuli-responsive nanoplatforms for efficient delivery of drugs in an on-demand manner show promising potential for killing cancer cells with high accuracy and minimal invasiveness. Herein, taking advantage of the good tissue-penetrating depth of sonodynamic therapy (SDT), reactive oxygen species (ROS)-responsive nanoscale coordination polymers (NCPs) were designed through self-assembly of porphyrins (PP) and platinum, which contained ROS-cleavable thioketal (TK) linkers to enhance the release of doxorubicin (Dox) during SDT. Upon exposure to the ultrasound (US), the Dox-loaded NCPs (PTK@PEG/Dox) could generate high amounts of cytotoxic ROS and heat, which not only induced the apoptosis of MCF-7 cells but also facilitated the efficient release of Dox due to the decomposition of the ROS-sensitive TK linkers, achieving the synergistic therapy of US-induced therapy and chemotherapy. After being modified with Arg-Gly-Asp (RGD) peptide, RGD/PTK@PEG exhibited a good targeting ability to cancer cells. Importantly, using the multicellular tumor spheroids (MCTS) derived from MCF-7 cells as a model, the RGD/PTK@PEG/Dox exhibited an efficient and controlled release behavior of Dox under the US irradiation, accompanying a tremendous anti-cancer effect for inducing apoptosis in the solid tumor tissues. This work provided a potential strategy to design controllable and stimuli-responsive nanoplatforms for synergistic/enhanced US-induced cancer therapy. Stimulus-responsive nanoplatforms can deliver drugs efficiently in an on-demand manner, showing the potential to kill cancer cells with high accuracy and minimal invasiveness. Taking advantage of the good penetration ability of ultrasound (US), nanoscale coordination polymers (NCP) composed of porphyrin (PP), thioketal (TK) linkers, and platinum(II) were prepared via a coordination-driven self-assembly procedure. After doxorubicin (Dox) was loaded on the NCP (PTK@PEG/Dox), the nanoplatform responded to reactive oxygen species (ROS) under the stimulation of US, and induced the on-demand release of Dox, thereby achieving the combined therapeutic effect of sonodynamic therapy (SDT) and chemotherapy for cancer. This work provides a potential strategy for the development of controllable and stimuli-responsive nanoplatforms for enhanced ultrasound-induced cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • GNRs@Void@PPy yolk@shell nanostructures with tunable void space have been fabricated. • Synergistic enhancement of photothermal performance of GNRs@Void@PPy has been achieved. • The manipulation of the void space has offered GNRs@Void@PPy with high drug encapsulation efficiency. • The GNRs@Void@PPy holds great promise for tumor treatment through chemo-photothermal synergistic therapy. Synergistic therapy has been emerging as new trend for effective tumor treatment due to synchronous function and cooperative reinforcement of multi therapeutic modalities. Herein, gold nanorods (GNRs) encapsulated into polypyrrole (PPy) shell with tunable void space (GNRs@Void@PPy) showing yolk@shell nanostructures were innovatively designed. The exploitation of dual near-infrared (NIR) absorptive species offered synergistic enhancement of photothermal performance. In addition, the manipulation of the void space between them provided additional benefits of high drug encapsulation efficiency (92.6%) and, interestingly, tumor microenvironment and NIR irradiation triggered targeted drug releasing. Moreover, the GNRs@Void@PPy exhibited excellent biocompatibility, and optimal curative effect by chemo-photothermal synergistic therapy was achieved through both in vitro and in vivo antitumor activity investigation. [ABSTRACT FROM AUTHOR]

Background: Cancer is the most serious world's health problems on the global level and various strategies have been developed for cancer therapy. Pillar[5]arene-based supramolecular therapeutic nano-platform (SP/GOx NPs) was constructed successfully via orthogonal dynamic covalent bonds and intermolecular H-bonds with the assistance of glucose oxidase (GOx) and exhibited efficient targeted/synergistic chemo-chemodynamic cancer therapy. Methods: The morphology of SP/GOx NPs was characterized by DLS, TEM, SEM and EDS mapping. The cancer therapy efficinecy was investigated both in vivo and in vitro. Results: SP/GOx NPs can load drug molecules (Dox) and modify target molecule (FA-Py) on its surface conveniently. When the resultant FA-Py/SP/GOx/Dox NPs enters blood circulation, FA-Py will target it to cancer cells efficiently, where GOx can catalyst the overexpressed glucose to generate H2O2. Subsequently, the generated H2O2 in cancer cells catalyzed by ferrocene unit to form •OH, which can kill cancer cells. Furthermore, the loaded Dox molecules released under acid microenvironment, which can further achieve chemo-therapy. Conclusion: All the experiments showed that the excellent antitumor performance of FA-Py/SP/GOx/Dox NPs, which provided an new method for pillar[5]arene-based supramolecular polymer for biomedical applications. [ABSTRACT FROM AUTHOR]

Background: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies. Result: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect. Conclusion: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy. [ABSTRACT FROM AUTHOR]

The lysosome is a prominent and crucial target for actualizing anticancer therapy due to the outstanding therapeutic effect of lysosomal cell death on apoptosis‐ and drug‐resistance cancer. Exploration of multifunctional materials involving lysosome‐targeting drugs for achieving efficient cancer treatment is definitely appealing, yet a significantly challenging task. Herein, a versatile nanotheranostic system allowing all cancer cell‐targeting, tumor microenvironment stimuli‐responsive, fluorescence imaging, lysosome‐targeting chemotherapy and nucleus‐targeting chemotherapy functions was tactfully designed and constructed, by encapsulating both doxorubicin and a lysosome‐specific targeting drug with aggregation‐induced emission features in functional amphiphilic polymers. Both in vitro and in vivo studies revealed that the presented nanotheranostic system exhibited synergistic anticancer therapy effects, negligible systemic toxicity, and remarkable inhibition of drug‐resistant cancer cells. This study thus brings a new insight into the development of a superior effective protocol for practical cancer treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The preferred cancer treatment is to achieve a high therapeutic effect as well as reduce side effects. In this study, we developed carrier-free nano drugs based on 5-fluorouracil (5FU) and cinnamaldehyde (CA) to meet the above goals. Two model drugs were spliced by acetal linkage and ester bond, which could self-assemble into nano drug particles (5FU–CA NPs) with a size of ∼170 nm. In vitro cell experiments showed 5FU–CA NPs were efficiently internalized by HepG2 cells. They then quickly exerted dual drug activities by the cleavage of acetal and ester bond, resulting in enhanced cell-killing efficacy and apoptosis. Synergistic mechanisms were achieved via the anti-metabolic effects mediated by 5FU–COOH and the oxidative damage induced by CA. In vivo anti-tumor evaluation further indicated that 5FU–CA NPs had higher tumor growth inhibition than 5FU–COOH/CA mixture (5FU–COOH + CA) and exhibited lower systemic toxicity under the same reducing dose of each drug. Overall, this is a successful synergistic anti-tumor attempt through rational self-assembly of drugs with different mechanisms and it can be extrapolated to other agents. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of oral nanotherapeutics against colorectal cancer (CRC) is restricted by inadequate drug accumulation, immunosuppressive microenvironment, and intestinal microbiota imbalance. To overcome these challenges, we elaborately constructed 6-gingerol (Gin)-loaded magnetic mesoporous silicon nanoparticles and functionalized their surface with mulberry leaf-extracted lipids (MLLs) and Pluronic F127 (P 127). In vitro experiments revealed that P 127 functionalization and alternating magnetic fields (AMFs) promoted internalization of the obtained P 127 -MLL@Gins by colorectal tumor cells and induced their apoptosis/ferroptosis through Gin/ferrous ion-induced oxidative stress and magneto-thermal effect. After oral administration, P 127 -MLL@Gins safely passed to the colorectal lumen, infiltrated the mucus barrier, and penetrated into the deep tumors under the influence of AMFs. Subsequently, the P 127 -MLL@Gin (+ AMF) treatment activated antitumor immunity and suppressed tumor growth. We also found that this therapeutic modality significantly increased the abundance of beneficial bacteria (e.g., Bacillus and unclassified -c-Bacilli), reduced the proportions of harmful bacteria (e.g., Bacteroides and Alloprevotella), and increased lipid oxidation metabolites. Strikingly, checkpoint blockers synergistically improved the therapeutic outcomes of P 127 -MLL@Gins (+ AMF) against orthotopic and distant colorectal tumors and significantly prolonged mouse life spans. Overall, this oral therapeutic platform is a promising modality for synergistic treatment of CRC. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer treatment is presently a significant challenge in the medical domain, wherein the primary modalities of intervention include chemotherapy, radiation therapy and surgery. However, these therapeutic modalities carry side effects. Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as promising modalities for the treatment of tumors in recent years. Phototherapy is a therapeutic approach that involves the exposure of materials to specific wavelengths of light, which can subsequently be converted into either heat or Reactive Oxygen Species (ROS) to effectively eradicate cancer cells. Due to the hydrophobicity and lack of targeting of many photoresponsive materials, the use of nano-carriers for their transportation has been extensively explored. Among these nanocarriers, liposomes have been identified as an effective drug delivery system due to their controllability and availability in the biomedical field. By binding photoresponsive materials to liposomes, it is possible to reduce the cytotoxicity of the material and regulate drug release and accumulation at the tumor site. This article provides a comprehensive review of the progress made in cancer therapy using photoresponsive materials loaded onto liposomes. Additionally, the article discusses the potential synergistic treatment through the combination of phototherapy with chemo/immuno/gene therapy using liposomes. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The water-soluble IR783 molecules can collaborate with the hydrophobic curcumin (Cur) to form carrier-free nanodrug delivery system via π-π stacking. • The yielded nanodrug delivery system exhibited efficient near-infrared fluorescence imaging on tumor and enhanced chemo-photothermal anti-tumor synergistic effect in vivo. • The carrier-free nanodrug delivery system had excellent biocompatibility and blood safety. 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. [ABSTRACT FROM AUTHOR]

Background: Reactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy. Methods: Indocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model. Results: Compared with DOX·HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX·HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed. Conclusions: Lipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy. [ABSTRACT FROM AUTHOR]

The past several years have witnessed the blooming of emerging immunotherapy, as well as their therapeutic potential in remodeling the immune system. Nevertheless, with the development of biological mechanisms in oncology, it has been demonstrated that hypoxic tumor microenvironment (TME) seriously impairs the therapeutic outcomes of immunotherapy. Hypoxia, caused by Warburg effect and insufficient oxygen delivery, has been considered as a primary construction element of TME and drawn tremendous attention in cancer therapy. Multiple hypoxia-modulatory theranostic agents have been facing many obstacles and challenges while offering initial therapeutic effect. Inspired by versatile nanomaterials, great efforts have been devoted to design hypoxia-based nanoplatforms to preserve drug activity, reduce systemic toxicity, provide adequate oxygenation, and eventually ameliorate hypoxic-tumor management. Besides these, recently, some curative and innovative hypoxia-related nanoplatforms have been applied in synergistic immunotherapy, especially in combination with immune checkpoint blockade (ICB), immunomodulatory therapeutics, cancer vaccine therapy and immunogenic cell death (ICD) effect. Herein, the paramount impact of hypoxia on tumor immune escape was initially described and discussed, followed by a comprehensive overview on the design tactics of multimodal nanoplatforms based on hypoxia-enabled theranostic agents. A variety of nanocarriers for relieving tumor hypoxic microenvironment were also summarized. On this basis, we presented the latest progress in the use of hypoxia-modulatory nanomaterials for synergistic immunotherapy and highlighted current challenges and plausible promises in this area in the near future. Cancer immunotherapy, emerging as a novel treatment to eradicate malignant tumors, has achieved a measure of success in clinical popularity and transition. However, over the last decades, hypoxia-induced tumor immune escape has attracted enormous attention in cancer treatment. Limitations of free targeting agents have paved the path for the development of multiple nanomaterials with the hope of boosting immunotherapy. In this review, the innovative design tactics and multifunctional nanocarriers for hypoxia alleviation are summarized, and the smart nanomaterial-assisted hypoxia-modulatory therapeutics for synergistic immunotherapy and versatile biomedical applications are especially highlighted. In addition, the challenges and prospects of clinical transformation are further discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Cisplatin is one of the most used first-line anticancer drugs for various solid tumor therapies. However, cisplatin-based chemotherapy can induce tumor cells to secrete excessive prostaglandin E2 (PGE2) catalyzed by cyclooxygenase-2 (COX-2), which, in turn, counteracts its chemotherapeutic effect and further accelerates tumor metastasis. Here, we report a carrier-free self-delivered nanoprodrug based on platinum (II) coordination bonding coupled with tolfenamic acid (Tolf) (named Tolfplatin). Tolfplatin can spontaneously assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. Compared with cisplatin, Tolfplatin NPs can facilitate cellular uptake, significantly decrease PGE2 secretion by COX-2 inhibition, which further downregulate tumorous anti-apoptotic and metastasis-associated proteins, thereby efficiently inducing apoptotic cell death and significantly inhibit tumor metastasis in vitro and in vivo. Therefore, as the carrier-free nanoprodrug, Tolfplatin NPs are promising anti-tumoral agents to inhibit tumor proliferation and metastasis by enriching the function and promoting the anti-tumor activity of cisplatin. Unlabelled Image • An anti-inflammatory dual-functional anticancer prodrug (named Tolfplatin) was synthesized through platinum (II) coupled with Tolfenamic acid by coordination bonding. • Tolfplatin can self-assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. • Tolfplatin NPs not only functions as anti-tumor drug but also exerts the anti-inflammatory as well as anti-metastasis effect. • Tolfplatin NPs can significantly prolong the survival time of tumor-bearing mice compared with cisplatin. [ABSTRACT FROM AUTHOR]

The development of versatile nanotheranostic platforms that integrate both diagnostic and therapeutic functions have always been an intractable challenge in precise cancer treatment. Herein, an aptamer‐tethered deoxyribonucleic acids‐gold particle (Apt‐DNA‐Au) nanomachine has been developed for in situ imaging and targeted multimodal synergistic therapy of mammary carcinoma. Upon specifically internalized into MCF‐7 cells, the tumor‐related TK1 mRNA activates the Apt‐DNA‐Au nanomachine by DNA strand displacement cascades, resulting in the release of the fluorophore and antisense DNA as well as the aggregation of AuNPs for in situ imaging, suppression of survivin expression and photothermal therapy, respectively. Meanwhile, the controlled released drugs are used for chemotherapy, while under the laser irradiation the loaded photosensitizer produces reactive oxygen species (ROS) for photodynamic therapy. The results confirm that the proposed Apt‐DNA‐Au nanomachine provides a powerful nanotheranostic platform for in situ imaging‐guided combinatorial anticancer therapy. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) represents a promising modality that provides the possibility of non-invasively eliminating solid tumors in a site-directed manner. In light of the complexity and heterogeneity of tumors, more and more studies are attempting to combine SDT with other therapeutic methods so as to achieve better tumor treatment effect, which sheds new light on the potential of SDT-based synergistic therapeutics. Herein, the representative studies of SDT-instructed multimodal synergistic cancer therapy are comprehensively presented, such as sono-chemotherapy, sono-radiotherapy, sono-immunotherapy, and sono-chemodynamic therapy, etc., and their incorporate mechanisms are discussed in detail. The current challenges and future prospects to promote the advanced development of SDT-based nanomedicines in this burgeoning research field are highlighted. It is believed that such an emerging synergistic therapeutic modality based on SDT will play a more significant role in the field of tumor precision treatment medicine. [ABSTRACT FROM AUTHOR]

A multifunctional nanodrug, PAMAM@CuS-HA-RB/DOX, was prepared for the real time tracking and chemo-photothermal therapy of tumor cells. The CuS nanoclusters with diameter less than 10 nm could be easily ingested by tumor cells and showed good colloid stability and high photothermal conversion efficiency. The hyaluronic acid (HA) coating and rhodamine B (RB) labeling endowed the nanocomposite with low cytotoxity and real time fluorescence imaging ability. In the acidic tumor microenvironment, the doxorubicin linked via the pH-responsive hydrazone bonds was released and worked synergistically with CuS to kill the tumor cells, which showed a high chemo-photothermal therapy capacity. All these properties indicated the PAMAM@CuS-HA-RB/DOX have promising application for the therapy of cancers and tracking of nanodrugs. A multifunctional nanodrug, PAMAM@CuS-HA-RB/DOX, was prepared for the real-time tracking and chemo-photothermal therapy of tumor cells. The nanocomposite with diameter less than 10 nm could be easily uptaken by tumor cells, and showed good colloid stability, high photothermal conversion efficiency, and good chemo-photothermal therapy capacity. [ABSTRACT FROM AUTHOR]

Although multimodal cancer therapy has shown superior antitumor efficacy in comparison to individual therapy due to the potential generation of synergistic interactions among the treatments, its clinical usage is highly hampered by systemic dose-limiting toxicities. Herein, we developed a multi-responsive nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and gold nanoparticles (AuNPs) (abbreviated as ACA) to combine chemotherapy, radiotherapy (RT) and photothermal therapy. The nanocomplex markedly improved the efficiency of drug delivery where ACA resulted in noticeably higher tumor growth inhibition than free cisplatin. The tumor treated with ACA showed an increased heating rate upon 532 nm laser irradiation, indicating the photothermal conversion ability of the nanocomplex. While RT alone resulted in slight tumor growth inhibition, thermo-chemo therapy, chemoradiation therapy and thermo-radio therapy using ACA dramatically slowed down the rate of tumor growth. Upon 532 nm laser and 6 MV X-ray, the nanocomplex could enable a trimodal thermo-chemo-radio therapy that yielded complete tumor regression with no evidence of relapse during the 90-days follow up period. The results of this study demonstrated that the incorporation of AuNPs and cisplatin into alginate hydrogel network can effectively combine chemotherapy, RT and photothermal therapy to achieve a locally synergistic cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Tumor recurrence in patients after surgery severely reduces the survival rate of surgical patients. Targeting and killing recurrent tumor cells and tissues is extremely important for the cancer treatment. Results: Herein, we designed a nano-biomimetic photothermal-controlled drug-loading platform HepM-TSL with good targeting ability and immunocompatibility for the treatment of recurrent hepatocellular carcinoma. HepM-TSL can accurately target the recurrent tumor area with the aid of the cloaked homotypic cell membrane and release the chemotherapy drugs in a controlled manner. In vivo results have confirmed that HepM-TSL loaded with drugs and photosensitizer achieves the synergistic treatment of recurrent hepatocellular carcinoma with good therapeutic effect and slight side effects. Conclusion: Accordingly, HepM-TSL provides a sound photothermal-chemotherapy synergistic strategy for the treatment of other recurrent cancers besides of recurrent hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Two‐dimensional (2D) nanomaterials are currently explored as novel photothermal agents because of their ultrathin structure, high specific surface area, and unique optoelectronic properties. In addition to single photothermal therapy (PTT), 2D nanomaterials have demonstrated significant potential in PTT‐based synergistic therapies. In this Minireview, we summarize the recent progress in 2D nanomaterials for enhanced photothermal cancer therapy over the last five years. Their unique optical properties, typical synthesis methods, and surface modification are also covered. Emphasis is placed on their PTT and PTT‐synergized chemotherapy, photodynamic therapy, and immunotherapy. The major challenges of 2D photothermal agents are addressed and the promising prospects are also presented. [ABSTRACT FROM AUTHOR]

Protein-based nanocarriers with inherent biocompatibility have been widely served as building blocks to construct versatile therapeutic nanoplatforms. Herein, bovine serum albumin-iridium oxide nanoparticles (denoted BSA-IrO2 NPs) are successfully synthesized via one-step biomineralization approach. The BSA-IrO2 NPs exhibits uniform size (40 nm), superb biocompatibility and high drug loading capacity for doxorubicin (27.4 wt%). Under near-infrared (NIR) laser irradiation, the as-prepared BSA-IrO2 NPs exhibited high photothermal conversion ability (54.3%) and good photostability. The in vitro drug release experiments displayed pH and NIR laser -triggered DOX release profiles, which could enhance the therapeutic anticancer effect. By utilizing this DOX loaded nanoplatform, effective synergistic chemo-photothermal therapy against human osteosarcoma can be realized, which has been systematically verified both in vitro and in vivo. Notably, in vivo pharmacokinetics studies showed that BSA-IrO2@DOX had prolonged blood circulation time due to the BSA component can improve the stealthiness of the nanoparticles during the blood circulation. Meanwhile, in vitro and in vivo toxicity studies demonstrated that the BSA-IrO2 NPs can act as biocompatible agents for drug delivery and cancer therapy. Therefore, this work presents a biomineralized iridium-based NPs with remarkable features and be used as a very potential therapeutic nanoplatform for cancer treatment. [ABSTRACT FROM AUTHOR]

The nanomaterials with enzyme-like catalytic activity, named as nanozymes, have aroused wide research interest owing to their striking merits. Metal-organic frameworks (MOFs) have showed great prospect in the construction of novel nanozymes. In this review, firstly, we summarize the most recent contributions in the design construction of the MOFs-based nanozymes. Then, we concentrate our attention on their applications in the fields of sensing and cancer therapies. According to the design strategies, we categorized MOFs-based nanozymes into four classes for review (i.e. pristine MOFs, MOFs with modification, MOFs-based nanocomposites, and MOF derivatives). Meanwhile, the emerging and fascinating 2D MOFs-based nanozymes were also reviewed. A variety of novel applications are also discussed, including nanozymes catalytic mediated signal amplification in sensing applications (e.g. colorimetric sensing, fluorescent sensing, chemiluminescent sensing, electrochemical sensing, and surface-enhanced Raman scattering (SERS)), and nanozymes catalytic mediated cancer therapy (i.e. cancer-starvation therapy, enhancing photodynamic therapy, and cancer-starvation and PDT synergistic therapy). At the end of the article, future opportunities and challenges in this promising research area are tentatively proposed. The design construction of MOFs-based nanozymes and the applications of the MOFs-based nanozymes to sensing and cancer therapy. Image 1 • Progress in the design construction of MOFs-based nanozymes was reviewed. • The applications of MOFs-based nanozymes to sensing were summarized. • The applications of MOFs-based nanozymes in cancer therapy were summarized. • The challenges and opportunities of MOFs-based nanozymes are put forward. [ABSTRACT FROM AUTHOR]

Synergistic therapy that combines drug/siRNA for the solid tumor treatment is becoming more and more popular to reduce the side effects and enhance the antitumor efficiency. Given that, a novel injectable supramolecular hydrogel mPECT(D)/GDDC-4(R)/α-CDgel (mPECT(D) represents DOX-loaded methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone) (mPECT) nanoparticles, GDDC-4(R) represents siBcl-2-loaded PG-P(DPAx-co-DMAEMAy)-PCB (GDDC-4) complexes nanoparticles (NPs)) was prepared via the incorporation of GDDC-4/siRNA complexes NPs into the DOX-loaded mPECT NPs/α-CDgel formed by the host-guest interaction between mPEG and α-CD. In vitro degradation and release experiments revealed that siBcl-2 was released from mPECT(D)/GDDC-4(R)/α-CDgel in the form of GDDC-4/siBcl-2 complexes NPs with bioactivity, and the release behavior of DOX also demonstrated sustained-release property. Compared to the single treatment groups, the enhanced cytotoxicity to SKOV3 and HeLa cells of mPECT(D)/GDDC-4(R)/α-CDgel was observed in vitro. Moreover, in vivo experiments also indicated the significant antitumor effect of mPECT(D)/GDDC-4(R)/α-CDgel, suggesting the remarkable synergistic therapy of DOX and siBcl-2. Therefore, this work would provide a prospective platform to co-delivery of drugs and siRNA to improve the treatment effect of solid tumor. [ABSTRACT FROM AUTHOR]

Abstract Using metal oxide semiconductor nanomaterials for synergistic cancer treatment has recently attracted the attention of numerous researchers. Herein, oxygen-defective vanadium oxide nanodots (VO x NDs) with ultra-small size and great dispersibility were synthesized via a novel user-friendly method, and then doxorubicin was loaded onto the VO x NDs surfaces. The VO x NDs had great photothermal conversion efficiency and stability. Doxorubicin-loaded VO x NDs can simultaneously serve as therapeutic agent and tumor microenvironment-activable HSP60 inhibitor, resulting in improved efficacy of photothermal therapy and released active doxorubicin for chemotherapy. Finally, we show that synergistic treatment achieved significant therapeutic effects in mice. These results provided a promising strategy for developing novel methods of synthesizing metal oxide semiconductors for enhanced synergistic cancer treatment. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Carrier-free nanodrugs named BCNPs were prepared by the coassembly of 2,5-bis(4-(diethylamino)benzylidene)cyclopentanone (BDBC) and curcumin (CCM) in the absence of surfactants. The as-synthesized BCNPs possess high dispersity and stability in aqueous media, along with favorable photostability and good biocompatibility. Comparing with their counterparts BDBC and CCM, BCNPs exhibit higher singlet oxygen yield and better two-photon photodynamic therapy (PDT) efficacy. Moreover, BCNPs display dramatically enhanced ability for inhibiting the growth of HeLa cells, which benefits from the synergistic treatment of BDBC and CCM under the irradiation of 450/808 nm. This work highlights the potential of using simple coassembly strategy to codelivery of multiple drugs in one single formulation for cancer therapy. [ABSTRACT FROM AUTHOR]

Ca2+ overload is one of the most widely causes of inducing apoptosis, pyroptosis, immunogenic cell death, autophagy, paraptosis, necroptosis, and calcification of tumor cells, and has become the most valuable therapeutic strategy in the field of cancer treatment. Nevertheless, several challenges remain in translating Ca2+ overload-mediated therapeutic strategies into clinical applications, such as the precise control of Ca2+ dynamics, specificity of Ca2+ homeostasis dysregulation, as well as comprehensive mechanisms of Ca2+ regulation. Given this, we comprehensively reviewed the Ca2+-driven intracellular signaling pathways and the application of Ca2+-based biomaterials (such as CaCO 3 -, CaP-, CaO 2 -, CaSi-, CaF 2 -, and CaH 2 -) in mediating cancer diagnosis, treatment, and immunotherapy. Meanwhile, the latest researches on Ca2+ overload-mediated therapeutic strategies, as well as those combined with multiple-model therapies in mediating cancer immunotherapy are further highlighted. More importantly, the critical challenges and the future prospects of the Ca2+ overload-mediated therapeutic strategies are also discussed. By consolidating recent findings and identifying future research directions, this review aimed to advance the field of oncology therapy and contribute to the development of more effective and targeted treatment modalities. Ca 2+ overload-mediated synergistic therapy: This review comprehensively overviewed the Ca2+-involved intracellular biological functions, and the application of calcium-involved biomaterials in mediating cancer diagnosis, treatment or immunotherapy. Meanwhile, the latest researches of Ca2+ overload-mediated therapeutic strategies, and combined with multiple-model therapies in mediating cancer immunotherapy are further highlighted, as well as the critical challenges and future directions are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • Reaction mechanism, influencing factor, and natural shortcoming of conventional PDT. • Strategies for construction of the optimized UCNP-PS systems for efficient UC-PDT. • Representative examples of UC-PDT combining with some traditional anti-cancer methods. • Guidance for design and synthesis of the future new UCNP-PS for synergistic UC-PDT. Abstract Photodynamic therapy (PDT) has become widely accepted and utilized for tumor therapy. Considering the natural shortcomings (e.g., lack of an ideal photosensitizer and limited light penetration depth), lanthanide doped upconversion nanoparticles (Ln-doped UCNP), which can be excited with near-infrared light (NIR) for UV/visible/NIR upconversion luminescence (UCL) emissions, show great potential for augmenting biological treatment with PDT for solid tumors and for visual bioimaging of disease lesions. This review summarizes the basic concepts and important influence factors on PDT, the optimized construction of UCNP-based photosensitizer (UCNP-PS) systems, and some representative examples of UCNP-based PDT (UC-PDT) applications in combination with other traditional therapy methods, such as chemotherapy, radiotherapy, photothermal therapy (PTT) and gene therapy. This review will provide guidance for the design and fabrication of future new UCNP-based nanocomposites for synergistic UC-PDT therapy. [ABSTRACT FROM AUTHOR]

Co-delivery of two drugs with diverse physicochemical properties and specific administration order for cancer theranostics are vitally important for drug resistance conquering and side effects reducing. Consequently, we explored a unique amphiphilic PCL-AuNC/Fe(OH) 3 -PAA Janus nanoparticle (JNP) to simultaneously preserve the hydrophilic drug (doxorubicin) and hydrophobic drug (docetaxel) in their distinct domains. Owing to their extraordinary heterostructure and independent pH and NIR sensitive properties, the optional sequential drug release by a single inorganic JNP was realized for the first time, and the results presented the synchronous release of two drugs had 5% better therapeutic effect. In addition, the excellent computed X-ray tomography/magnetic resonance (CT/MR) imaging capabilities from AuNC and Fe(OH) 3 suggested our JNPs could effectively guide the cancer therapy. Furthermore, the mice treated with dual drug loaded PCL-AuNC/Fe(OH) 3 -PAA JNPs under near infrared (NIR) laser irradiation showed better tumor inhibition than solo drug, cocktail and dual drug treated groups, indicating the effectivity and significance of combined cancer therapy. [ABSTRACT FROM AUTHOR]