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M2-type macrophages (M2Φ) play a pro-tumorigenic role and are closely associated with tumor development, where metabolic dysregulation exacerbates the immunosuppressive tumor microenvironment and fosters tumor growth. Mitochondria serve as the regulatory center of cellular metabolism, yet effective methods to modulate M2Φ mitochondria within the tumor microenvironment remain lacking. In this study, we developed a technique utilizing the bio-encapsulation of mitochondria in Zeolitic Imidazolate Framework-8 (ZiF-8), referred to as Mito@ZiF-8. Our findings demonstrated that this coating protects intact mitochondria and preserves their bioactivity over an extended period after isolation. We successfully delivered Mito@ZiF-8 into M2Φ, which inhibited the secretion of pro-inflammatory factors, promoted the release of anti-inflammatory factors, and reprogrammed M2Φ metabolism. This innovative approach has the potential to reduce breast cancer cell metastasis and enhance sensitivity to chemotherapy drugs such as 6-thioguanine, cisplatin, and doxorubicin (Dox). Mito@ZiF-8 aims to reprogram the M2Φ microenvironment to support anti-tumor therapies, offering a novel strategy for improving the effectiveness of breast cancer treatment.

Despite the use of surgical resection and chemotherapy in the clinical treatment of oral squamous cell carcinoma (OSCC), the 5-year survival rates of advanced patients are low. Therefore, more efficient strategies are urgently needed. Herein, a chemo/ferroptosis synergistic therapeutic system-DMEFe nanoparticles (NPs) is established for the treatment of OSCC. To create this system, the chemotherapeutic agent doxorubicin (DOX) was loaded into mesoporous silica nanoparticles and further coated with a pH-sensitive metal polyphenol (iron ion and epigallocatechin gallate). These nanoparticles displayed excellent pH-sensitive drug-control release properties, and the release ratio of DOX at pH 5.5 was twice as high than that at pH 7.4. Additionally, DMEF NPs were effectively taken up by the OSCC cell line SSC-25, which greatly impeded the proliferation of these cells. Notably, these nanoparticles increased the intracellular level of reactive oxygen species and effectively exhibited cytotoxity effects. The mechanistic results proved that DMEFe NPs regulated the expression of ferroptosis-related genes to induce ferroptosis of SSC-25 cells. Eventually, this chemo/ferroptosis therapeutic system exhibited remarkable antitumor effects and provided a novel strategy for the treatment of OSCC.

Stimuli-responsive nanoscale polymer-drug conjugates are one of the most promising alternatives in the realm of advanced therapeutics, rendering several characteristics such as spatio-temporal control over drug release, reduced off-target toxicity, enhanced bioavailability, and longer blood circulation time of the drug. Fostered by the aforementioned conceptualization, our quest to develop an ideal polymer-drug conjugate has originated the present investigation of developing a reactive oxygen species (ROS) and esterase-responsive self-assembled polymer-drug (chlorambucil, CBL) conjugate with biotin pendants (DP2) for cancer cell targeting, surrogating another antineoplastic drug, doxorubicin (DOX) via physical encapsulation (DP2@DOX). The ROS and esterase trigger not only released the covalently stitched CBL but also resulted in DOX release by dismantling the amphiphilic balance of the nanoaggregates. Biotinylation-mediated enhancement of cellular uptake of DP2@DOX was reflected in the synergistic anticancer activity of both the drugs (CBL and DOX) in HeLa cells (biotin receptor-positive cells) compared to HEK 293T cells (biotin receptor-negative cells). Furthermore, the selective internalization of the fluorophore-tagged DOX-loaded polymer (DP4@DOX) in HeLa cells compared to HEK 293T cells was confirmed by confocal microscopy and flow cytometry. In summary, the present investigation demonstrates a state-of-the-art self-assembled polymer-drug conjugate as a next-generation dual stimuli-responsive drug delivery vehicle.

Nanoparticles (NPs) derived from branched copolymers of poly (β-L-malic acid) (PMLA) have been extensively investigated for drug delivery due to their high density of pendant carboxyl groups. This abundant functional group availability enhances their potential as effective drug delivery systems; however, the strong negative charge of PMLA poses a challenge in its uptake by cancer cells due to electrostatic repulsion. In this study, we developed novel enzyme- and pH-sensitive nanoparticles (EP-NPs) based on PMLA, demonstrating tumor-specific behavior and selective activation within tumor tissues. To enhance the cellular internalization of the nanoparticles, we incorporated transactivator of transcription (TAT). In summary, long-chain polyethylene glycol (PEG) was conjugated to PMLA to confer specificity to the TAT peptide. This was achieved using a tetrapeptide linker: alanine-alanine-asparagine-leucine (AANL), which serves as a substrate for legumain. Legumain is a highly conserved cysteine protease primarily found in lysosomes and blood vessels, initially discovered in legumes. It is markedly overexpressed in numerous solid tumors, as well as in endothelial cells and tumor-associated macrophages. The release of doxorubicin in tumor cells was sustained due to the low pH (5.0-5.5) and degradation of PMLA. The PEG modification optimized the particle size and shielded the nanoparticles from plasma proteins and detection by the reticuloendothelial system, thereby prolonging their long circulation time. Once the nanoparticles reached the tumor microenvironment, the AANL was cleaved by legumain, exposing the TAT peptide on the surface, which enhances cellular internalization. Both in vitro and in vivo efficacy studies demonstrated that these EP-NPs significantly inhibited tumor growth while exhibiting negligible systemic toxicity, thereby suggesting that the developed enzyme/pH-sensitive PMLA-based nanoparticle holds great promise as an anti-tumor drug delivery system.

Although chemotherapy with magnetic nanocarriers has witnessed significant advancement in the field of cancer treatment, multimodal diagnosis and combinatorial therapy using a single nanoplatform will have much better efficacy in achieving superior results. Herein, we constructed a smart theranostic system by combining pH-sensitive tartaric acid-stabilized Fe 3 O 4 magnetic nanocarriers (TMNCs) with SPECT imaging and a chemotherapeutic agent for image-guided chemo-hyperthermia therapy. The carboxyl-enriched exteriors of TMNCs provided sites for the conjugation of a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and radiolabeling ( 141 Ce). The usage of 145.4 keV gamma rays made this platform an ideal choice for in vivo SPECT-CT imaging, showing the retention of the nanoformulation in the tumor site even after 28 days. Further, TMNCs showed a very high transverse relaxation rate ( r 2 ) of 171 mM -1 s -1 , which is higher than that of clinically approved magnetic resonance imaging (MRI) contrast agents such as ferumoxtran (65 mM -1 s -1 ) and ferumoxides (120 mM -1 s -1 ). Further, the developed drug-loaded hybrid platform showed significantly higher cytotoxicity towards breast cancer cells, which was augmented by in vitro magnetic hyperthermia. Bright-field microscopy and cell cycle analysis suggested that cell death occurred through induction of G2-M arrest and subsequent apoptosis. These findings clearly suggest the potential of the developed hybrid nanoplatform for image-guided combination therapy.

Polymeric nanocarriers have attracted significant attention in the field of anticancer drug delivery due to their unique advantages. However, designing nanocarriers that can maintain stability in the bloodstream while achieving specific drug release within tumor cells remains a major challenge. To address this issue, constructing reversible cross-linked polymeric nanocarriers that are sensitive to the intracellular reducible glutathione (GSH) characteristic of the tumor microenvironment is a promising strategy. Based on this, we designed and synthesized two novel six-membered bicyclic carbonate monomers containing disulfide (DSBC) and trisulfide (TSBC) bonds. Through a one-step ring-opening polymerization, a series of reduction-sensitive polycarbonate copolymers (i.e., PEG-PDSBC and PEG-PTSBC) were prepared, and doxorubicin (DOX)-loaded nanoparticles were fabricated using a nanoprecipitation method. The in vitro drug release behaviors of these nanoparticles were systematically investigated. The results showed that these polymers, due to the cross-linked structure formed by the ring-opening polymerization of their bicyclic monomers, could self-assemble into stable nanoparticles. Under different concentrations of glutathione, DOX-loaded PEG-PTSBC nanoparticles demonstrated faster drug release, indicating more optimized intracellular drug release properties. Further cytotoxicity experiments revealed that both types of blank nanoparticles exhibited good biocompatibility with the 4T1 and NIH-3T3 cells. Fluorescence microscopy and flow cytometry results further indicated that DOX-loaded PEG-PTSBC nanoparticles released more drugs in 4T1 cells, significantly inhibiting tumor cell growth compared with DOX-loaded PEG-PDSBC nanoparticles, with no noticeable difference in NIH-3T3 normal cells. In conclusion, this study suggests that trisulfide cross-linked polycarbonate-based nanocarriers hold promise as an anticancer drug delivery system that combines stability in the bloodstream with specific intracellular drug release, offering new insights for the development of novel, efficient, and safe anticancer nanomedicines.

Extracellular vesicles (EVs) have shown great promise as drug delivery system (DDS). However, their complex and costly production limit their development for clinical use. Interestingly, the plant kingdom can also produce EV-like nanovesicles that can easily be isolated and purified from a large quantity of raw material at a high yield. In this study, olive-derived nanovesicles (ODNVs) were isolated from raw fruits using serial centrifugations and their physical and biological features characterized to demonstrate their promising potential to be used as a DDS. Nanotracking particle analysis indicated an average size of 109.5 ± 3.0 nm and yield of 10 12 ODNVs/mL for the purest fraction. Microscopy imaging, membrane fluidity assay and lipidomics analysis showed the presence of a rich lipid bilayer that significantly varied between different sources of ODNVs but showed a distinct signature compared to human EVs. Moreover, ODNVs were enriched in PEN1 and TET8 compared to raw fruits, suggesting an extracellular origin. Interestingly, ODNVs size and yield stayed unchanged after exposure to high temperature (70 °C for 1 h), wide pH range (5-10), and 50-100 nm extrusion, demonstrating high resistance to physical and chemical stresses. This high resistance allowed ODNVs to stay stable in water at 4 °C for a month, or with the addition of 25 mM trehalose for long-term freezing storage. Finally, ODNVs were internalized by both 2D and 3D cell culture without triggering significant cytotoxicity and immunogenicity. Importantly, the anticancer drug doxorubicin (dox) could be loaded by passive incubation within ODNVs and dox-loaded ODNVs decreased cell viability by 90% compared to only 70% for free dox at the same concentration, indicating a higher efficiency of drug delivery by ODNVs. In addition, this high cytotoxicity effect of dox-loaded ODNVs was shown to be stable after a 2-week storage at 4 °C. Together, these findings suggested that ODNVs represent a promising candidate as drug nanocarrier for various DDS clinical applications, as demonstrated by their biocompatibility, high resistance to stress, good stability in harsh environment, and improvement of anticancer drug efficacy., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors agreed to publish this manuscript. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

This work reports a new nano platform made from natural materials for phototherapy (PT) applications. For this purpose, calcium carbonate nanoparticles (NPs) derived from Persian Gulf squid bones as a drug carrier, Syzygium cumini (dye extracted from the fruit of the Persian Gulf trees) as a photosensitizer, and Doxorubicin as a chemotherapy (CHT) drug have been used. In addition, copper NPs were added to the above nanocomposition to increase the efficiency of photothermal (PTT) treatment. For PT, samples were irradiated by an 808 nm laser (1 W cm -2 ). The results show that nanocomposites play an influential role in the reactive oxygen species process, and an increase of 21 degrees in temperature during 15 min of laser radiation is effective in photodynamic (PDT)/PTT therapy. The drug loading capacity of the nanocomposite was calculated as 49%. This new nanocomposite for simultaneous PDT/PTT/CHT holds great promise for future cancer treatment due to its excellent potential in treatment and reduced systemic toxicity., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

In this study, we examined the self-assembly of a series of biodegradable and biocompatible amino acid-based polyhydroxyurethanes (PHUs), investigating the structural influence of these polymers on their self-assembly and the resulting morphological features. The presence of hydrophilic and hydrophobic segments, along with carbonyl urethane, ester, and hydroxyl groups in the PHU backbone, facilitates intermolecular hydrogen bonding, enabling the formation of self-assemblies with hierarchical nanodimensional morphologies. We determined the critical aggregation concentration (CAC) and found that it largely depends on the PHU's structure. In-depth morphological studies demonstrated that the evolution of morphology proceeds in four steps: (1) the initial formation of micelles, which act as seeds at very low concentrations, (2) the elongation of these micelles into nanorod or nanopalette shapes below the CAC range, (3) the epitaxial growth of nanofibers at the CAC, and (4) the complete formation of fibrous mats above the CAC. Additionally, these hierarchical structures were utilized for the encapsulation and release of the drug doxorubicin (DOX). We observed that 75% of the encapsulated DOX was readily released in a mildly acidic environment, similar to the physiological conditions of cancer cells. Cellular uptake studies confirmed the effective uptake of the drug-loaded nanoassemblies into the cytoplasm of cells. Our studies also confirmed that these self-assembled structures can serve as effective cell adhesive scaffolds for tissue engineering applications.

Lung adenocarcinoma is considered to be one of the primary causes of cancer-related deaths globally. Conventional treatments, such as chemotherapy and radiation therapy taken together, have not significantly lowered mortality rates. Repositioning of authorized anticancer medications supported by nanotechnology has therefore emerged as an effective strategy to close such gaps. In this context, mesoporous silica nanoparticles (MSNs) were biosynthesized from cucumber peels and were loaded with doxorubicin, a common anticancer drug to form doxorubicin-bound mesoporous silica nanoparticles (DMSNs). The study addresses a sustainable method for turning waste materials into MSNs, which can be used to create multifunctional nanosystems. The therapeutic module (DMSNs) was designed specifically to target 2D monolayer cells and 3D tumor spheroids of lung adenocarcinoma cancer. The DMSNs demonstrated notable antiproliferative activity and effective intracellular localization in addition to being biocompatible and innately fluorescent. Subsequent investigations revealed significant antibacterial activity against Staphylococcal infection, which is primarily prevalent in lung cancer patients. Thus, the developed MSNs held promising potential for anticancer drug delivery systems and have antibacterial potential to treat bacterial infections in patients with lung cancer. Furthermore, the cucumber peel-mediated synthesis of MSNs could also aid in the management of food waste and promote the adoption of the waste-to-health paradigm for sustainable solutions.

Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody combining facile chemical modification and Sortase A-mediated site-specific ligation, as demonstrated by the development of an epidermal growth factor receptor (EGFR)-targeted drug delivery system. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH 2 -GG-PEG2000-DSPE, by hydrophobic insertion. The diglycine as nucleophiles displayed on the membrane enabled the subsequent ligation of the EGFR nanobody (7D12) by Sortase A (SrtA)-mediated site-specific transpeptidation. The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. In conclusion, these results demonstrate that 7D12-functionalized BmExo can serve as a target-specific delivery system for Dox to selectively kill EGFR-expressing tumor cells. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo., (© 2024 Wiley-VCH GmbH.)

Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, its practical application is still suffering from the decreased function and inadequate infiltration of NK cells in the immunosuppressive microenvironment of solid tumors. Herein, we construct light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on the NK cell surface, a catalytic array with light-harvesting capabilities is formed. This functionality transforms NK cells into cellular factories capable of catalyzing the production of active agents in a light-controlled manner. NK@p-Fe can generate the active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, NK@p-Fe can also bioorthogonally catalyze the production of the FDA-approved immune agonist imiquimod (IMQ). The activated immune agonist plays a dual role, inducing dendritic cell maturation for NK cell activation and reshaping the tumor immunosuppressive microenvironment for NK cell infiltration. This work represents a paradigm for the modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis., (© 2024 Wiley-VCH GmbH.)

Stimuli-responsive nanoplatforms have been popular in controlled drug delivery research because of their ability to differentiate the tumor microenvironment from the normal tissue environment in a spatiotemporally controllable manner. The synergistic therapeutic approach of combining cancer chemotherapy with photothermal tumor ablation has improved the therapeutic efficacy of cancer therapeutics. In this study, a UiO-66 metal organic framework (MOF)-based system loaded with doxorubicin (DOX), surface decorated with the photothermal agents indocyanine green (ICG) and polydopamine (PDA), and conjugated with transferrin (TF) was successfully designed to operate as a responsive system to pH changes, featuring photothermal capabilities and target specificity for the purpose of treating breast cancer. The synthesized nanoplatform benefits from its uniform size, excellent DOX encapsulation efficiency (91.66 %), and efficient pH/NIR-mediated controlled release of the drug. In vitro photothermal studies indicate excellent photothermal stability of the formulation even after 6 on-off cycles of NIR irradiation. The in vitro cytotoxicity assessment using an NIR laser (808 nm) revealed that the DOX-loaded functionalized UiO-66 nanocarriers had outstanding inhibitory effects on 4T1 cells because of synergistic chemo-photo therapies, with no substantial toxicity by the carriers. In addition, cellular uptake evaluations revealed that UiO-DOX-ICG@PDA-TF could specifically target 4T1 cells on the basis of receptor-mediated internalization of transferrin receptors. Additionally, in vivo toxicity studies in Wistar rats indicated no signs of significant toxicity. The UiO-based nanoformulations effectively inhibited and destroyed cancer cells under 808 nm laser irradiation because of their minimal toxicity, strong biocompatibility, and outstanding synergistic chemo/photothermal/photodynamic 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. Published by Elsevier B.V.)

Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe 3 O 4 )-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening., 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.)

Targeted breast cancer therapies hold the potential to improve the efficiency of drug delivery to the pathology site without impacting the viability and function of healthy cells. Herein, we developed multifunctional nanocarriers that target simultaneously several downstream signaling processes in triple negative breast cancer cells. The system comprises pH sensitive CaCO 3 nanoparticles (NPs) as carriers of the anticancer drug doxorubicin (DOX). The NPs were coated in a layer-by-layer (LbL) fashion using poly-l-lysine and hyaluronic acid to target receptors overexpressed in breast cancer (e.g. CD44, RHAMM). Spheroids of the triple-negative Hs578T cell line were used as a 3D model to assess the therapeutic potential of this system. Our results showed that the NPs act via a synergistic mechanism that combines Ca 2+ overload causing cell calcification and DNA damage by DOX. The LbL coating was crucial for the protection of the healthy cells, i.e. it provides NPs with targeting capacity. The overall data suggests that the LbL-coated NPs loaded with DOX hold great potential for the treatment of breast cancer., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

The clinical efficacy of cancer vaccines is closely related to immunoadjuvants that play a crucial role in magnifying and prolonging the immune response. Muramyl dipeptide (MDP), a minimal and conserved peptidoglycan found in almost all bacteria, can trigger robust immune activation by uniquely antagonizing the nucleotide-binding oligomerization domain 2 (NOD2) pathway. However, its effectiveness has been hindered by limited solubility, poor membrane penetration, and rapid clearance from the body. Here, we introduce MDP-presenting polymersomes as artificial nanobacteria (NBA) to boost the antitumor immune response. The NBA, featuring abundant MDP molecules, induces superior stimulation of immune cells including macrophages and bone marrow-derived dendritic cells (BMDCs) compared to free MDP, likely via facilitating immune cell uptake and cooperatively stimulating systemic NOD2 signaling. Importantly, systemic administration of NBA significantly enhances the chemo-immunotherapy of B16-F10 melanoma-bearing mice pretreated with doxorubicin by reversing the immunosuppressive tumor microenvironment. Furthermore, NBA carrying ovalbumin and B16-F10 cell lysates induces robust OVA-IgG antibody production and effectively inhibit tumor growth, respectively. The artificial nanobacteria hold great promise as a potent systemic immunoadjuvant for cancer immunotherapy.

Despite advancements in nanomedicine for drug delivery, many drug-loaded nanoparticles reduce tumor sizes but often fail to prevent metastasis. Mesoporous silica nanoparticles (MSNs) have attracted attention as promising nanocarriers. Here, we demonstrated that MSN-PEG/TA 25, with proper surface modifications, exhibited unique antimetastatic properties. In vivo studies showed that overall tumor metastasis decreased in 4T1 xenografts mice treated with MSN-PEG/TA 25 with a notable reduction in lung tumor metastasis. In vitro assays, including wound-healing, Boyden chamber, tube-formation, and real-time cell analyses, showed that MSN-PEG/TA 25 could modulate cell migration of 4T1 breast cancer cells and interrupt tube formation by human umbilical vein endothelial cells (HUVECs), key factors in suppressing cancer metastasis. The synergistic effect of MSN-PEG/TA 25 combined with liposomal-encapsulated doxorubicin (Lipo-Dox) significantly boosted mouse survival rates, outperforming Lipo-Dox monotherapy. We attributed the improved survival to the antimetastatic capabilities of MSN-PEG/TA 25. Moreover, Dox-loaded MSN-PEG/TA 25 suppressed primary tumors while retaining the antimetastatic effect, thereby enhancing therapeutic outcomes and overall survival. Western blot and qPCR analyses revealed that MSN-PEG/TA 25 interfered with the phosphorylation of ERK, FAK, and paxillin, thus impacting focal adhesion turnover and inhibiting cell motility. Our findings suggest that drug-free MSN-PEG/TA 25 is highly efficient for cancer treatment via suppressing metastatic activity and angiogenesis.

The combination of chemotherapy and photodynamic therapy holds immense potential for achieving synergistic anti-tumor efficacy. However, challenges such as poor stability and premature drug release prior to reaching tumor sites impede the widespread application of this synergistic therapeutic approach. In this study, a novel ATP-responsive NIR fluorescence nanosystem (CDZ) for imaging-guided chemotherapy and PDT has been developed. This nanosystem, based on ZIF-90, encapsulates the chemotherapy drug doxorubicin (DOX) and the photosensitizer asymmetrical cyanine dye Cy through self-assembly. The obtained nanosystem CDZ could efficiently avoid premature drug leakage in the blood circulation due to its high stability in the physiological environment and accumulates at the tumor sites via the enhanced permeability and retention (EPR) effect. Upon uptake by tumor cells, the skeleton structure of CDZ is disrupted by overexpressed ATP levels, leading to the release of DOX, which inhibits cancer cell proliferation and induces cell death. Additionally, the released photosensitizer Cy emits strong NIR fluorescence signals, enabling real-time imaging of ATP levels in tumors. Moreover, under NIR light irradiation, this nanosystem generates high levels of ROS, achieving effective phototherapy even in deeper tumor regions. In tumor model mice, CDZ demonstrated a high rate of tumor inhibition without causing damage to major organs. This ZIF-based NIR fluorescence nanosystem, combining chemotherapy and photodynamic therapy, holds promise as a solution for treating and monitoring cancer without the associated risks of resistance and systemic toxicity.

Treatment of local tumor recurrence and repair of the tissue defects after tumorectomy still remain clinical challenges. Currently, controlled release of therapeutic drugs is one of the widely used approaches to kill the residual and recurrent cancer cells, and stem cell-laden hydrogel scaffolds are promising candidates for soft tissue repair. However, hydrogel scaffolds with the bifunction of controlled release of therapeutic drugs for cancer therapy and loading stem cells for tissue repair are still not well established. In this study, we fabricated a biphasic hydrogel scaffold containing two types of core/shell filaments with drugs and stem cells loaded in the core part of these two filaments. Black phosphorus nanosheets were added to alginate (the shell layer) in the drug-loaded filament, endowing the scaffold with a photothermal effect under near infrared (NIR) laser irradiation. Moreover, NIR could trigger the drug release from the core/shell filaments to achieve photothermal-chemotherapy of cancer. Additionally, stem cells embedded in the core parts of the other filaments could maintain high cell viability due to the protection of the shell layer (pure alginate), which promoted soft tissue regeneration in vivo . Thus, the prepared biphasic scaffold with drug- and stem cell-laden core/shell filaments may be a potential candidate to fill the tissue defects after the surgical resection of tumors to kill the residual and recurrent cancer and repair the tissue defects.

Cancer, a pressing global health challenge, is characterized by its rapid onset and high mortality rates. Conventional treatment methods prove insufficient in achieving the desired therapeutic outcomes, underscoring the critical need to identify an effective and safe approach for cancer treatment. In this study, a copper-doped nanoparticle known as Cu 2+ -DOX@ZIF-90 is designed by incorporating copper(II) (Cu(II)) and encapsulating doxorubicin (DOX) within ZIF-90. Leveraging the elevated ATP levels in cancer cells relative to normal cells, Cu 2+ -DOX@ZIF-90 undergoes intracellular degradation, leading to the release of DOX and Cu(II). DOX, a traditional chemotherapy drug for clinical use, induces apoptosis in cancer cells. Cu(II) interacts with glutathione (GSH) to generate Cu(I), catalyzing H 2 O 2 to produce ˙OH, thereby prompting apoptosis in cancer cells. Concurrently, the reduction of GSH enhances the therapeutic effect of chemodynamic therapy (CDT). Furthermore, Cu(II) triggers the aggregation of lipoylated mitochondrial proteins, leading to the formation of DLAT oligomers and ultimately promoting cuproptosis in cancer cells. In vivo experimental findings demonstrate that Cu 2+ -DOX@ZIF-90 does not cause damage to normal tissues and organs in tumor-bearing mice, with a notable tumor inhibition rate of 86.18%. This synergistic approach, combining chemotherapy, CDT, and cuproptosis, holds significant promise for the effective and safe treatment of cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous, lacks accessible therapeutic targets, and features an immunosuppressive tumor microenvironment (TME). Anthracycline-based chemotherapy remains the primary treatment method for TNBC, while the current popular immune checkpoint inhibitors persistently encounter therapeutic resistance. Therefore, there is an urgent need to explore combined therapeutic strategies to remodel the TME and improve the treatment response. Considering the highly specific homing ability of tumor cell-derived vesicles and the key role of the signal transduction and activation of the transcription factor 3 (STAT3) pathway in TNBC, we propose a synergistic therapeutic strategy that integrates gene therapy, chemotherapy, and immunotherapy based on STAT3 short interfering RNA (siSTAT3) and doxorubicin (DOX)-functionalized tumor-derived extracellular vesicles (TEVs) (siSTAT3-DOX@TEV). The in vitro and in vivo results demonstrate that siSTAT3-DOX@TEV target tumor tissues precisely, downregulate STAT3 expression, and synergistically and efficiently induce immunogenic death, thereby reversing the immunosuppressive TME. Moreover, mass cytometry and immunohistochemistry reveal the local immune activation effect of siSTAT3-DOX@TEV, with a significant increase in M1 macrophages, CD4 + T cells, and CD8 + T cells in tumor tissues. These results provide strong hints for the development of TEV-based chemo-gene therapeutic agents for TNBC treatment at the clinical level.

Introduction: Tumor drug resistance and systemic toxicity are major challenges of modern anticancer therapy. Nanotechnology makes it possible to create new materials with the required properties for anticancer therapy., Methods: In this research, Dextran-graft-Polyacrylamide/ZnO nanoparticles were used. The study was carried out using prostate (DU-145, LNCaP, PC-3), breast (MDA-MB-231, MCF-7, MCF-7 Dox) cancer cells and non-malignant (MAEC, BALB/3T3 clone A31) cells. Zinc was visualized with fluorescence in vitro and in vivo. ROS and apoptotic markers were identified by cytometry. Zinc accumulation and histopathological changes in the tumor, liver, kidney, and spleen were evaluated in a rat model., Results: ZnO nanoparticles dissociation and release of Zn 2+ into the cytosol occurs in 2-3 hours for cancerous and non-cancerous cells. ROS upregulation was detected in all cells. For non-malignant cells, the difference between the initial ROS level was insignificant. The rate of carbohydrate metabolism in cancer cells was reduced by nanosystems. Zinc level in the tumor was upregulated by 25% and 39% after treatment with nanosystems and doxorubicin combined, respectively. The tumor Walker-256 carcinosarcoma volume was reduced twice following mono-treatment with the nanocomplex and 65-fold lower when the nanocomplex was combined with doxorubicin compared with controls. In the liver, kidney and spleen, the zinc level increased by 10-15% but no significant pathological alterations in the tissues were detected., Conclusion: D-PAA/ZnO NPs nanosystems were internalized by prostate, breast cancer cells and non-malignant cells via endocytosis after short time, but cytotoxicity against non-cancer cells were significantly lower in vitro and in vivo. D-PAA/ZnO NPs nanocomplex efficiently promoted cell death of tumor cells without showing cytotoxicity against non-malignant cells making it a promising anti-cancer agent., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Virych et al.)

A drug delivery system based on silybin-conjugated chitosan (CS-SB) polymeric micelles was developed to improve the oral absorption of doxorubicin (DOX). SB was grafted to CS via succinic acid, and CS-SB was identified by 1 H NMR and FT-IR. The DOX-loaded micelles were prepared by self-assembly, and the characteristics of micelles, including a small particle size of 167.8 ± 2.3 nm, a high drug loading capacity of 8.59%, and a low critical micelle concentration of 1.3 × 10 -5 g/mL, were demonstrated. The micelles showed oral bioavailability of up to 193% versus DOX·HCl. The cytotoxicity test showed the biosafety of CS-SB and the potential of reductive DOX-induced cardiotoxicity. The inhibition of P-gp efflux and CYP3A4 enzyme in CS-SB micelles was confirmed by cellular uptake and enzyme activity inhibition tests. The endocytosis process of micelles was revealed by an endocytosis inhibition test. The findings exhibited the potential of CS-SB micelles in drug delivery.

Targeted cancer therapy using nanocarriers has emerged as a promising solution to the majority of drawbacks associated with conventional chemotherapy. The present research work describes the development of folic acid (FA)-targeted redox responsive [S-(PLA- b -PEG-CONH)] 2 polymeric nanoparticles for the co-delivery of pirarubicin (Pira) and salinomycin (Sal). The nanoparticles' redox responsiveness arises from embedded disulfide bonds within the polymer, which gradually break in response to high GSH levels in tumors, enabling sustained drug release. The nanoparticles exhibited a hydrodynamic size of ∼104 nm and a surface charge density of -15.5 mV with low PDI values. Blank nanoparticles (w/o drug) showed negligible toxicity towards both non-malignant human and murine cells and exhibited excellent stability under different environmental conditions for up to 3 weeks. A cellular internalization study conducted using Rho B/C6 dual-dye-encapsulated nanoparticles showed efficient uptake of the nanoparticles after just 1 hour of incubation with SUM-149 2D adherent cells and 3D spheroids. The release of Pira and Sal from Pira/Sal dual-loaded nanoparticles increased significantly in a reducing environment. The % cumulative release of Pira increased from 20.5% ± 1.0 in PBS (pH 7.4) to 40.1% ± 0.4 in dithiothreitol (DTT) after 20 days; similarly, the % cumulative release of Sal increased from 36.2% ± 1.7 in PBS (pH 7.4) to 51.5% ± 1.7 in DTT. The cytotoxicity studies of FA-targeted Pira/Sal dual-loaded nanoparticles with varying Pira : Sal ratios (1 : 1, 3 : 1 and 1 : 3) revealed that the nanoparticles displayed 8-10 fold lower IC 50 values than the respective free drug formulations across multiple breast cancer cell lines including SUM-149, MDA-MB-231 and EAC as well as in 3D mammospheres. Balb/c syngeneic mice bearing EAC tumors experienced ∼100% tumor regression upon treatment with FA-targeted Pira/Sal (3 : 1) dual-loaded nanoparticles, indicating synergistic anti-tumor potency. In vivo survival and histopathological studies indicated no significant toxicity in vital organs of the body as compared to free drugs. Based on the performance, the currently investigated FA-targeted Pira/Sal dual-loaded nano-formulation is recommended to be further explored in other cancer types as well as in higher animals for cancer therapy.

Nanocarriers are frequently used for drug delivery due to their large surface area, biocompatibility, and photothermal effects. However, they face the problem of premature drug leakage during drug transport. To address this challenge, we developed near-infrared light (NIR)-responsive hollow magnetic nanocarriers (HMC) by incorporating a chitosan-based molecular valve onto hollow magnetic nanocarriers (CHMC) to enable NIR-triggered drug release. Despite this advancement, this material still encounters the challenge of inadequate targeting. Recognizing the efficacy of magnetically driven micro/nanorobot swarms in remote wireless control, targeted motion, and efficient transport, we merged CHMC with magnetically controlled micro/nanorobot swarms. We evaluated their performance under programmable magnetic fields, which can be precisely controlled in biological fluid and directed toward targeting cells. Additionally, they demonstrated the ability to execute a responsive drug release under NIR irradiation. Ultimately, we confirmed their capacity for targeted delivery, responsive drug release, and photothermal therapy for liver cancer treatment in vivo. This approach heralds new possibilities for responsive drug therapy facilitated by micro/nanorobot swarms, offering promising advancements in medical treatment.

Multimodal cancer therapies are often required for progressive cancers due to the high persistence and mortality of the disease and the negative systemic side effects of traditional therapeutic methods. Thus, the development of less invasive modalities for recurring treatment cycles is of clinical significance. Herein, a light-activatable microparticle system was developed for localized, pulsatile delivery of anticancer drugs with simultaneous thermal ablation by applying controlled ON-OFF thermal cycles using near-infrared laser irradiation. The system is composed of poly(caprolactone) microparticles of 200 μm size containing molybdenum disulfide (MoS 2 ) nanosheets as the photothermal agent and hydrophilic doxorubicin or hydrophobic violacein, as model drugs. Upon irradiation, the nanosheets heat up to ≥50 °C leading to polymer softening and release of the drug. MoS 2 nanosheets exhibit high photothermal conversion efficiency and require low-power laser irradiation. A machine learning algorithm was applied to acquire the optimal laser operation conditions. In a mouse subcutaneous model of 4T1 triple-negative breast cancer, 25 microparticles were intratumorally administered, and after 3-cycle laser treatment, the system conferred synergistic phototherapeutic and chemotherapeutic effects. Our on-demand, pulsatile synergistic treatment resulted in increased median survival up to 39 days post start of treatment compared to untreated mice, with complete eradication of the tumors at the primary site. Such a system is therapeutically relevant for patients in need of recurring cycles of treatment on small tumors, since it provides precise localization and low invasiveness and is not cross-resistant with other treatments.

Purpose: Chemotherapy is one of the most commonly used treatments for oral squamous cell carcinoma (OSCC), but its use is limited by drug resistance and severe systemic toxicity. To eliminate these side effects and improve anti-tumor efficacy, several therapeutic approaches have been developed for use with chemotherapy. In this study, we developed a graphene-based lipid modulation nanoplatform (NSD) that carries SB-204990, a small molecule inhibitor specific for ATP citrate lyase (ACLY), and doxorubicin (DOX), a chemotherapeutic agent, and the trio enables synergistic treatment of OSCC with lipid starvation, chemotherapy, and photothermal therapy., Methods: We first determined whether ACLY expression was upregulated in OSCC, and then assessed the growth inhibitory effects of SB-204990 on SCC-15 cells and changes in lipid (acetyl coenzyme A, free fatty acids, and cholesterol) levels. We characterized NSD and then evaluated the stability, photothermal properties, drug loading, and release ability of NSD. Finally, the therapeutic effects of NSD on OSCC were investigated by in vitro and in vivo experiments, and the changes in lipid levels in OSCC tissues after ACLY inhibition were further evaluated., Results: The results showed that ACLY was highly expressed in OSCC, and ACLY inhibition produced reproductive suppression and decreased lipid levels in SCC-15 cells. The NSD nanoplatform possessed good stability, photothermal properties, high drug loading capacity and controlled release. In addition, the triple therapy achieved satisfactory anticancer effects in both in vivo and in vitro assays, and the inhibition rate of tumors was as high as 99.4% in the NSD+Laser treatment group., Conclusion: The changes in tumor cell lipid levels and cell proliferation arrest induced by ACLY inhibition suggest that ACLY may be a promising target for lipid starvation therapy and resistance to chemoresistance, and its inhibitors are expected to become new anticancer drugs. The NSD nanocarrier system enables synergistic treatment with lipid starvation, chemotherapy, and photothermal therapy, which represents an innovative approach to combating tumors., Competing Interests: 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., (© 2024 Li et al.)

The work presents correlations between the physicochemical properties of the carrier and the active substance and optimization of the conditions for creating an active system based on PAMAM dendrimers and doxorubicin. The study monitored the influence of the ionized form of the doxorubicin molecule on the efficiency of complex formation. The deprotonated form of doxorubicin occurs under basic conditions in the pH range of 9.0-10.0. In the presence of doxorubicin, changes in the zeta potential of the complex concerning the initial system are observed. These changes result from electrostatic interactions between the drug molecules and external functional groups. Based on changes in the absorbance intensity of UV-vis spectra, the binding of the drug in the polymer structure is observed depending on the pH of the environment and the molar ratio. Optimal conditions for forming complexes occur under alkaline conditions. UV-vis, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy confirmed the stability of the formed dendrimer-DOX complex. Molecular dynamics simulations were conducted to gain a deeper insight into the molecular mechanism of DOX adsorption on and within the G4.0 PAMAM dendrimers. It was observed that the protonation state of both the dendrimer and DOX significantly influences the adsorption stability. The system exhibited high stability at high pH values (∼9-10), with DOX molecules strongly adsorbed on the dendrimer surface and partially within its bulk. However, under lower pH conditions, a reduction in adsorption strength was observed, leading to the detachment of DOX clusters from the dendrimer structure.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu 2+ . High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu 2+ to DOX, while that is about 10 wt % for PDHB without Cu 2+ . The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu 2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu 2+ depletes intracellular GSH and is reduced to Cu + simultaneously, which reacts with local H 2 O 2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

The applications of quarternized chitosans have achieved notable success in the development of drug-delivery systems. This study reported the preparation of quercetin-quarternized chitosan (Qu-QCS) conjugate and its application for the fabrication of stable and safe curcumin (cur) loaded nano-micelles with high targeting ability and selectivity towards the breast cancer cell lines. Moreover, doxorubicin (dox) was co-treated with the nanomicelles to enhance the efficacy and reduce the cardiotoxic effects of dox. Structural properties of Qu-QCS were evaluated by FTIR, DSC, and XRD analysis and the yield obtained was 48.82 %. The nano-micelles obtained showed spherical shape, <200 nm size, 48.38 % entrapment efficiency, prolonged stability at 4 °C and pH-responsive release pattern. The cur-loaded nano-micelles showed higher activity and selectivity against breast cancer (MCF-7 and MDA-MB-231) cell lines with enhanced internalization, lower toxicity to the normal cardiomyoctyes (H9C2), enhanced the cell cycle arrest at the G2/M phase of the breast cancer cell lines and induced apoptosis with high intensity compared to pure cur. Moreover, the co-treatment of dox with cur-loaded Qu-QCS nano-micelles showed increased anticancer activity and reduced cardiotoxicity. Overall, this study suggests the potential applications of cur-loaded Qu-QCS micelles in the delivery of chemotherapeutic agents and complementary support in combination with chemotherapeutic agents., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oral nano-drug delivery systems offering combination therapy have garnered significant interest in colon cancer treatment due to their precision in targeting tumors and minimizing peripheral tissue exposure. However, challenges such as the complex gastrointestinal environment and effective retention of nanoparticles in the colon have impeded further advancement. We developed a novel oral drug delivery system designed for localized treatment of colon cancer via chemotherapy and photothermal therapy (PTT). This system utilized mesoporous polydopamine (MPDA) as a photothermal carrier for doxorubicin hydrochloride (DOX), with surface modification using folic acid (FA) to enhance systemic tumor targeting. Additionally, to ensure gastrointestinal retention and precise colon localization, the nanoparticles were coated with an enteric-soluble material, ES100, resulting in the formulation MPDA-FA-DOX/ES100. This formulation exhibited high photothermal conversion efficiency, robust photothermal stability, and responsive drug release under near-infrared (NIR) laser stimulation. FA modification significantly enhanced the cellular uptake of nanoparticles by CT26 cells, promoting greater cytotoxic effects through combined chemotherapy and PTT. In vivo, MPDA-FA-DOX/ES100 demonstrated superior accumulation in colon tumor tissues and substantial photothermal effects, and notably, the CT/PTT group demonstrated significant tumor growth inhibition along with excellent biocompatibility. Collectively, these findings highlight the clinical potential of MPDA-FA-DOX/ES100 as an effective platform for localized and synergistic CT/PTT of colon cancer., Competing Interests: Declaration of competing interest The author 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 the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) facilitate drug resistance and tumor metastasis. Therefore, more and more attention has been focused on the regulation of TME by preventing the cross-talk between tumor cells and CAFs in the treatment of breast cancer. In this study, we have combined the benefits of deep drug penetration, pH sensitivity, and tumor-targeting delivery to prepare chondroitin sulphate (CS)-based nanomicelles (BBR/CS-DOX) for the co-delivery of doxorubicin (DOX) and berberine (BBR). A unique MCF-7 + MRC-5 co-cultured cell model and 4 T1 + NIH3T3 co-implanted mice model, were established to simulate the TME of breast cancer (BC). As expected, BBR/CS-DOX could accumulate in tumor egion, be taken up by both tumor cells and CAFs, and improve drug absorption and retention. Compared with free drugs, BBR/CS-DOX demonstrated stonger pro-apoptotic and anti-metastatic effect in vitro and in vivo, respectively the histological studies showed that BBR/CS-DOX efficiently prevented the activation of fibroblasts, inhibited extracellular matrix (ECM) deposition, and decreased tumor angiogenesis, showing superior anti-tumor efficacy. In summary, BBR/CS-DOX has the potential to significantly enhance the therapeutic effect of breast cancer through inhibiting the "CAFs-tumor cells" crosstalk, and has promising clinical application prospects., Competing Interests: Declaration of competing interest The author declares that there are no potential conflicts of interest regarding the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With the prevalence of drug-resistant bacteria and the waning effects of antibiotics, nanoplatform has become an effective strategy for fighting infections. This work reports a dipolar-hollowed α-Fe 2 O 3 @Au/Polydopamine (PDA) nanospindle which possesses both photothermal-photodynamic (PTT-PDT) coupling antibacterial and drug carrying performance. Firstly, the spindle type α-Fe 2 O 3 @Au/PDA particle was prepared by a simple one-step strategy and then the dipolar-hollow structure was obtained by controlling etching the inside α-Fe 2 O 3 core with hydrochloric acid. After further loading the photosensitizer zinc phthalocyanine (ZnPc), the dipolar-hollowed α-Fe 2 O 3 @Au/PDA-ZnPc nanospindles were obtained. Owing to the dipolar-hollowed interior, the nanospindles are also effective in carrying antitumor drug doxorubicin (DOX) and shows a good drug loading-release behavior. The dipolar-hollowed α-Fe 2 O 3 @Au/PDA nanospindles exhibits a high antibacterial performance against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) under near-infrared (NIR) and Xenon lamp irradiation. When α-Fe 2 O 3 @Au/PDA-ZnPc nanospindles concentration was increased to 100 μg/mL, the antibacterial rate was close to 100 %. In comparison to the original α-Fe 2 O 3 @Au/PDA nanospindles, the product achieved a lower effective antibacterial temperature. This triple-mode therapy (PTT/PDT/Drug) provides an interesting design idea for anisotropic therapeutic nanoplatform which can be applied in low-temperature antibacterial and drug delivery., 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.)

The early intervention of precancerous lesions of gastric cancer (PLGC) is crucial for improving the survival of patients with gastric cancer. Traditional pharmaceuticals for the treatment of PLGC are limited by side effects, thus developing innovative drug carrier that are more efficient but without the undesirable side effects is required. Here, we proposed an acid-triggered mushroom-derived β-glucan carrier embedding doxorubicin (DOX) to circumvent drug cytotoxicity and synergistically alleviate PLGC based on the controlled conformational transformation. The triple helix β-glucan extracted from Dictyophora rubrovolvata (DRP) loaded doxorubicin driven by pH and DMSO regulation, forming two rattan ball-like nanoparticles (DRP-DOX(pH) and DRP-DOX(DMSO)) via its collapse and recombination of triple-helix conformation. The findings revealed that DRP-DOXs achieved acid-triggerable and sustained drug delivery with an average particle size of 500 nm and 550 nm. In vitro evaluation of GES-1 cells showed DRP-DOXs reduced reactive oxygen species (ROS) production and altered mitochondrial membrane potential. Compared to DRP-DOX(DMSO) and DRP, DRP-DOX(pH) could more effectively downregulate cellular oxidative stress and inflammation to eventually alleviate PLGC, by regulating the p53 and PI3K pathways to mitigate gastric mucosa damage. Consequently, the nature-derived β-glucan delivery nanovesicle holds great promising applications in reducing drug toxicity and suppressing the development of PLGC., 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.)

Currently, traditional monotherapy for cancer often results in indiscriminate attacks on the body, leading to the emergence of new health problems. To confront these challenges, multimodal combination therapy has become necessary. However, how to develop new smart nanomaterials through green synthesis methods, delivering drugs while simultaneously synergizing multimodal combination therapies for tumor treatment, remains a topic of great significance. In this study, a biomimetic composite nanomaterial (RM-Cu/P) composed of mesoporous polydopamine (MPDA) as the core and red blood cell membranes (RBCMs) as the shell was synthesized as a drug carrier to deliver doxorubicin (DOX) while achieving synergistic chemotherapy, photothermal and chemodynamic therapy (CT/PTT/CDT). Herein, the nanoparticles were extensively characterized to examine their morphological characteristics, elemental composition, and drug-carrying capacity. Notably, the coating of RBCM reduced the toxicity of the RM-Cu/P@DOX nanoparticles, improved their targeting ability and prolonged their circulation time in vivo. The Cu-doped nanoparticles were capable of initiating a Fenton-like reaction to generate reactive oxygen species (ROS) for CDT, while the photothermal conversion efficiency (η) reached 45.20 % under NIR laser irradiation. Subsequently, the particles were examined by in vivo and in vitro experimental studies in cytotoxicity, cellular uptake, ROS levels, lysosomal escape, and mouse tumor model to evaluate their potential application in antitumor. Compared with monotherapy, the RM-Cu/P@DOX nanoparticles had multiple-stimulation response properties under redox, pH, and NIR, which exhibited the advantage of combined trimodal therapy, resulting in remarkable synergistic antitumor efficacy. In conclusion, this innovative platform exhibited promising applications in smart drug delivery and synergistic treatment of cancer., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hollow natural polysaccharide microcapsules have broad applications in drug delivery field due to their excellent biocompatibility and drug loading efficiency. In this paper, pH/near-infrared (NIR) dual-responsive microcapsules composed of hyaluronic acid (HA), chitosan (CS) and hollow CuS (HA/CS/HA@CuS) had been fabricated via a layer-by-layer (LbL) approach. The negative charge, rough surface and hollow structure of microcapsules are very favorable for loading positively charged DOX. As a result, hollow microcapsules display a high drug loading efficiency of 91.15 %. The variation in the degree of amino ionization at different pH values leads to the changes in the electrostatic force between CS/HA multilayers, resulting in the structural change in microcapsules. Therefore, microcapsules exhibit significant pH-responsive drug release properties. In addition, hollow CuS nanoparticles with excellent photothermal conversion ability are capped on the multilayer surface, enabling microcapsules to exhibit excellent NIR-responsive drug delivery properties. Overall, hyaluronic acid/chitosan-based hollow microcapsules with notable pH/NIR dual-responsiveness have been prepared, which can be used as a potential drug carrier for controlled drug delivery and photothermal chemical 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.)

Nanotechnology has emerged as a promising innovative avenue for therapeutic intervention in cancer research. However, achieving satisfactory accumulation of nanoparticles in the tumor and fabricating optimized nanoparticles remain challenging. In this work, we developed a novel polymeric micelle system to actively target integrin receptors, which are usually overexpressed in breast cancer. We first synthesized a targeted peptide-modified cyclic (Arg-Gly-Asp-D-Phe-Cys) (c(RGDfc))-polyethylene glycol-acitretin amphipathic conjugate (RPA) and prepared doxorubicin (DOX)-loaded RPADm (RPA@DOX) micelles with a high drug loading content of more than 11 %. Compared with unmodified DOX-containing micelles, RPADm demonstrated increased cytotoxicity and cellular uptake by MCF-7 cells. Importantly, competitive binding experiments confirmed that the observed enhancement effect was attributed to the modification of c(RGDfc) on the surface of the micelles. Furthermore, due to its active tumor-targeting ability, compared with the other DOX-based formulations, the RPADm exhibited the highest tumor distribution and strongest therapeutic efficacy in MCF-7 tumor-bearing nude mice. Additionally, the safety evaluation experiments revealed that the DOX-loaded micelles had no obvious systemic toxicity. These results suggest that the developed micelles modified with c(RGDfc) are promising candidates for tumor-active targeting therapies., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Numerous barriers hinder the entry of drugs into cells, limiting the effectiveness of tumor pharmacotherapy. Effective penetration into tumor tissue and facilitated cellular uptake are crucial for the efficacy of nanotherapeutics. Photodynamic therapy (PDT) is a promising approach for tumor suppression. In this study, we developed a size-adjustable porphyrin-based covalent organic framework (COF), further modified with hyaluronic acid (HA), to sequentially deliver drugs for combined chemo-photodynamic tumor therapy. A larger COF (P-COF, approximately 500 nm) was loaded with the antifibrotic drug losartan (LST) to create LST/P-COF@HA (LCH), which accumulates at tumor sites. After injection, LCH releases LST, downregulating tumor extracellular matrix (ECM) component levels and decreasing collagen density, thus reducing tumor solid stress. Additionally, the reactive oxygen species (ROS) generated from LCH under 660 nm laser irradiation induce lipid peroxidation of cell membranes. Owing to its larger particle size, LCH primarily functions extracellularly, paving the way for subsequent treatments. Following intravenous administration, the smaller COF (p-COF, approximately 200 nm) loaded with doxorubicin (DOX) and modified with HA (DOX/p-COF@HA, DCH) readily enters cells in the altered microenvironment. Within tumor cells, ROS generated from DCH facilitates PDT, while the released DOX targets cancer cells via chemotherapy, triggered by disulfide bond cleavage in the presence of elevated glutathione (GSH) levels. This depletion of GSH further enhances the PDT effect. Leveraging the size-tunable properties of the porphyrin COF, this platform achieves a multifunctional delivery system that overcomes specific barriers at optimal times, leading to improved outcomes in chemo-photodynamic multimodal tumor therapy in vivo., 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.)

The synergistic effect of apoptosis and cuproptosis, along with the activation of the immune system, presents a promising approach to enhance the efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: a reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX and a glutathione (GSH)-responsive prodrug PEG-DTPA-SS-CPT. These prodrugs are self-assembled and chelated Cu 2+ to prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), and Cu 2+ . The elevated levels of ROS and GSH in TNBC cells disrupted the PCD@Cu structure, leading to the release of Cu + , DOX, and CPT and the depletion of GSH. DOX and CPT triggered apoptosis with immunogenic cell death (ICD) in TNBC cells. Simultaneously, PCD@Cu downregulated the expression of copper transporting ATPase 2 (ATP7B), causing a significant accumulation of copper ions in TNBC cells. This further induced the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and downregulation of iron-sulfur (Fe-S) cluster proteins, ultimately leading to cuproptosis and ICD in TNBC. In vitro and in vivo experiments confirmed that PCD@Cu induced apoptosis and cuproptosis in TNBC and activated the immune system, demonstrating strong anti-tumor capabilities. Moreover, PCD@Cu exhibited an excellent biosafety profile. Overall, this study provides a promising strategy for effective TNBC therapy., (© 2024 Wiley‐VCH GmbH.)

Chalcones are a group of molecules with recognized biological potential against many diseases, including cancer. Thus, studies on this structure and derivatives have become an attractive chemical strategy to optimize their observed biological activities. One of the synthetic routes used to obtain chalcone derivatives is esterification using either commercial acid chlorides or carboxylic acids. This work focuses on preparing chalcone derivatives and investigating their biological potential against cancer cells. Compound 3'-hydroxychalcone (1) was synthetized by Claisen-Schmidt condensation followed by esterification of the 3'-OH, resulting in eight compounds named 1a-b and 2a-f. All structures were confirmed by 1 H and 13 C NMR and FT-IR, and cytotoxicity was evaluated in the HCT 116 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma), and CCD-18Co (nontumoral colon fibroblasts) cell lines. Chalcone derivatives were generally more active toward the colon cancer cell line, and 1a and 2b were selected for IC 50 determination, presenting IC 50 values of approximately 10 μM in HCT 116 cells and above 20 μM in both MCF7 and CDC-18-Co cells, suggesting moderate selectivity. Additionally, we tested compounds 1a and 2b in combination with doxorubicin, but they did not act synergistically with this anthracycline. In conclusion, considering these compounds obtained by the esterification reaction, 1a and 2d showed better results against cytotoxic cells., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Recently, the biocompatibility of hydrogel nanoparticles has gained considerable research attention in the field of drug delivery. In this regard, we design a pH-controlled nanocarrier based on magnetic layered double hydroxides/copper metal-organic framework-chitosan crosslinked к-carrageenan hydrogel nanoparticles (LDH-Fe 3 O 4 /Cu MOF-DOX-CS@CAR) for targeted release from DOX to breast cancer cells. FT-IR, EDX, XRD, FE-SEM, VSM, and Zeta potential investigated the chemical structure of hydrogel nanoparticles. The encapsulation efficiency and drug loading capacity of the DOX were obtained to be 96.1 % and 9.6 %, respectively. The cumulative release of DOX from LDH-Fe 3 O 4 /Cu MOF-DOX-CS@CAR at pH 5.5 and 7.4 after 72 h was 60.3 % and 22.6 %, respectively. These in vitro release results confirmed the controlled release and pH-response behavior of hydrogel nanoparticles. Also, the mechanism of DOX release from LDH-Fe 3 O 4 /Cu MOF-DOX-CS@CAR hydrogel nanoparticles showed that the Korsmeyer-Peppas model with Fickian diffusion is the best-fitting model for describing the release behavior of DOX from hydrogel nanoparticles. The cellular cytotoxicity and DAPI tests of the prepared LDH and LDH-Fe 3 O 4 /Cu MOF toward L929 non-cancerous cells and MCF-7 breast cancer cells confirm its relative biocompatibility and safety. Whereas, LDH-Fe 3 O 4 /Cu MOF-DOX-CS@CAR hydrogel nanoparticles toward MCF-7 breast cancer cells had higher cytotoxicity effects due to the targeted and controlled release of DOX to MCF-7 cells. The in vitro DPPH, hemolysis assay, colloidal stability, and enzymatic degradation proved the excellent antioxidant activity (71.81 %), blood compatibility (less than 5 %), better stability, and biodegradation behavior of hydrogel nanoparticles. On these findings, the present study suggests the potential of the prepared LDH-Fe 3 O 4 /Cu MOF-DOX-CS@CAR hydrogel nanoparticles as a pH-controlled drug delivery system for cancer treatment and various biomedical uses., 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. Conflicts of Interest The authors have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

It's currently a challenge to design a drug delivery system for chemotherapy with high drug contents and minimal side effects. Herein, we constructed a novel one-dimensional binary-drug delivery system for cancer treatment. In this drug delivery system, drugs (doxorubicin (DOX) and resveratrol (RES)) self-assemble on bacterial cellulose nano-whiskers (BCW) and are subsequently encapsulated by polydopamine (PDA) with high encapsulation efficiencies (DOX: 81.53 %, RES: 70.32 %) and high drug loading efficiencies (DOX: 51.54 %, RES: 36.93 %). The cumulative release efficiencies can reach 89.27 % for DOX and 80.05 % for RES in acidic medium within 96 h. The BCW/(DOX + RES)/PDA can enter tumor cells easily through endocytosis and presents significant anti-cancer effects. Furthermore, the released-RES plays a protective role in normal cells through up-regulation of antioxidant enzymes activities and scavenging of reactive oxygen species. Taken together, the one-dimensional BCW/(DOX + RES)/PDA binary-drug delivery system can be used for the anticancer treatment along with slight side effects., Competing Interests: Declaration of competing interest There are no conflicts of interest to be declared., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: This study was aimed at investigating the cytotoxic effect of a novel combination of doxorubicin (DOX) and nano-formulation of Santolina chamaecyparissus L. essential oil (SCEO-NANO) on hepatic (HepG2) and colon (HT29) cancer cell lines., Methods: A nano-emulsion was prepared by high-pressure homogenisation, then analysed by zetasizer and Fourier transform infrared spectroscopy. HepG2 and HT29 cells were used in in vitro tests for apoptosis detection., Results: Formulated droplet size increased in DOX@SCEO-NANO/DOX to 11.54 ± 0.02 with uniform distribution (PDI = 0.13 ± 0.01), when compared with SCEO-NANO (size: 8.91 ± 0.02 nm; PDI = 0.1 ± 0.02). In both cells, DOX@SCEO-NANO/DOX led to a considerable reduction in colony formation. Compared to DOX, apoprotein proteins were overexpressed in HepG2 cells, showing increases of 8.66-fold for caspase-3 and 4.24-fold for the Bax/Bcl-2 ratio. In HT29 cells, ROS-dependent necrosis and apoptosis were seen. Comparing DOX@SCEO-NANO/DOX versus DOX, greater levels of caspase-3 and the Bax/Bcl-2 ratio were observed., Conclusion: The DOX@SCEO-NANO/DOX formulation showed potential for targeted eradication of colon adenocarcinoma and hepatocellular carcinoma cells.

Advanced-stage liver cancers are associated with poor prognosis and have limited treatment options, often leading the patient to hospice care. Percutaneous intratumoral injection of anticancer agents has emerged as a potential alternative to systemic therapy to overcome tumor barriers, increase bioavailability, potentiate immunotherapy, and avoid systemic toxicity, which advanced-stage cancer patients cannot tolerate. Here, an injectable OncoGel (OG) comprising of a nanocomposite hydrogel loaded with an ionic liquid (IL) is developed for achieving a predictable and uniform tumor ablation and long-term slow release of anticancer agents into the ablation zone. Rigorous mechanical, physiochemical, drug release, cytotoxicity experiments, and ex vivo human tissue testing identify an injectable version of the OG with bactericidal properties against highly resistant bacteria. Intratumoral injection of OG loaded with Nivolumab (Nivo) and doxorubicin (Dox) into highly malignant tumor models in mice, rats, and rabbits demonstrates enhanced survival and tumor regression associated with robust tissue ablation and drug distribution throughout the tumor. Mass cytometry and proteomic studies in a mouse model of colorectal cancer that often metastasizes to the liver indicate an enhanced anticancer immune response following the intratumoral injection of OG. OG may augment immunotherapy and potentially improve outcomes in liver cancer patients., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Aim: To construct a novel liposomal drug delivery system co-modified with SP94 and BR2 ligands, encapsulating both the bitter ginseng derivative B21 and doxorubicin (DOX), to achieve superior anti-tumour efficacy and reduced toxic side effects., Methods: Liposomes were prepared using an organic phase reaction method, with B21 encapsulated in the lipid phase and DOX in the aqueous phase. The liposomes were further modified with SP94 and BR2 peptides. The characterisations, cytotoxicity, and in vitro targeting effects were assessed through various methods including ultraviolet spectrophotometry, high-performance liquid chromatography, nano-size analysis, ultrafiltration centrifugation, dialysis, transmission electron microscopy, flow cytometry, Methylthiazolyldiphenyl-tetrazolium bromide assay, confocal laser scanning microscopy, transwell assay, and tumorsphere assay., Results: SP94/BR2-B21/DOX-LP liposomes were spherical with an average diameter of 120.87 ± 1.00 nm, a polydispersity index (PDI) of 0.223 ± 0.006, and a surface charge of -23.1 ± 1.27 mV. The encapsulation efficiencies for B21 and DOX were greater than 85% and 97% (mg/mg), respectively. The results indicated that SP94/BR2-B21/DOX-LP exhibited enhanced targeting and cytotoxicity compared to single-ligand modified and unmodified liposomes, with the combined encapsulation of B21 and DOX showing synergistic anti-hepatocarcinogenic effects., Conclusion: SP94/BR2-B21/DOX-LP liposomes represent a promising targeted drug delivery system for hepatocellular carcinoma, offering improved membrane penetration, enhanced therapeutic efficacy, and reduced systemic toxicity.

The impact of optically active biomaterials on drug delivery remains a vital and hot topic. To reveal special advantages of optically active mesoporous silica nanoparticles in delivering drug in cells, optically active mesoporous silica nanoparticles deliver doxorubicin (DOX) with chiral behavior in cancer cells was studied. The present work focused on two types of optically active mesoporous silica nanoparticles named as levorotatory optically active mesoporous silica nanoparticles (LOA-MSNs) and dextrorotatory optically active mesoporous silica nanoparticles (DOA-MSNs) and examined their effects on cellular DOX delivery in cancer cells. The obtained LOA-MSNs and DOA-MSNs were regular spheres with particle diameters ranging from 200 to 250 nm, and their shell layer was filled with interlaced channels. Our results indicated that LOA-MSNs and DOA-MSNs did not exhibit cytotoxicity towards MCF-7 cells and B16 cells. The cytotoxicity of DOX-loaded LOA-MSNs and DOX-loaded DOA-MSNs were stronger than DOX owing to the synergistic retention and accumulation effect of nanoparticles. More importantly, DOX-loaded DOA-MSNs presented stronger cytotoxicity due to the higher synergistic retention and accumulation effect of DOA-MSNs. These findings suggest that DOA-MSNs with superior cellular delivery of DOX have great potential to advance the development of optical anti-tumor delivery system., (© 2024. Controlled Release Society.)

The transformation of monotherapy into multimodal combined targeted therapy to fully exploit synergistic efficacy is of increasing interest in tumor treatment. In this work, a novel nanodrug-carrying platform based on iron-based MOFs, which is loaded with doxorubicin hydrochloride (DOX), dihydroartemisinin (DHA), and glucose oxidase (GOx), and concurrently covalently linked to the photosensitizer 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) in polydopamine (PDA)-encapsulated MIL-101(Fe) (denoted as MIL-101(Fe)-DOX-DHA@TCPP/GOx@PDA, MDDTG@P), is successfully developed. Upon entering the tumor microenvironment, MDDTG@P catalyzes the hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (·OH) and depletes glutathione (GSH); thus, exerting the role of chemodynamic therapy (CDT). The reduced Fe 2+ can also activate DHA, further expanding CDT and promoting tumor cell apoptosis. The introduced GOx will rapidly consume glucose and oxygen (O 2 ) in the tumor; while, replenishing H 2 O 2 for Fenton reaction, starving the cancer cells; and thus, realizing starvation and chemodynamic therapy. In addition, the covalent linkage of TCPP endows MDDTG@P with good photodynamic therapeutic (PDT) properties. Therefore, this study develops a nanocarrier platform for triple synergistic chemodynamic/photodynamic/starvation therapy, which has promising applications in the efficient treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

Nanomedicines have been widely used in colorectal cancer treatment, but their suboptimal targeting and deficient penetration capabilities remain obstacles in the delivery of therapeutics. In this study, inspired by the natural tumor tropism and intestinal invasion of Salmonella , we engineered highly biomimetic nanoparticles (SM-AuNRs) utilizing a Salmonella membrane to coat bacilliform Au nanorods. The engineered SM-AuNRs were able to mimic the germ's morphology and biological surface. SM-AuNRs containing the specific proteins inherited from the Salmonella membrane facilitated specific targeting and internalization into tumor cells. Meanwhile, SM-AuNRs with the rod-shaped morphology effectively traversed mucus barriers and tumor stroma. Due to the superior biological barrier penetrating and tumor targeting capabilities, doxorubicin-loaded SM-AuNRs with near-infrared laser irradiation displayed remarkable photothermal-chemotherapeutic antitumor effects in mouse orthotopic colorectal cancer models. Our findings pave the way for the design of bacteria-mimicking nanoparticles, presenting a promising avenue for the targeting and efficient treatment of colorectal cancer.

Pyroptosis, a form of programmed cell death, holds great promise for breast cancer treatment. However, the downregulation of gasdermin E (GSDME) limits the effectiveness of pyroptosis. To address this challenge, we developed a folic acid-modified and glutathione/reactive oxygen species dual-responsive nanocarrier (FPSD NPs) for the targeted delivery of doxorubicin (DOX). Through the combination with DNA methyltransferase inhibitor decitabine (DAC), the GSDME protein expression was significantly increased in 4T1 cells, resulting in cell swelling and ballooning, which are characteristic features of pyroptosis. In vivo experiments further demonstrated the antitumor efficacy of DAC + DOX@FPSD NPs, and the 4T1-bearing mice treated with DAC + DOX@FPSD NPs exhibited reduced tumor volumes, minimized tumor weights, decreased Ki67-positive cells, increased TUNEL apoptosis ratios, and pronounced lesions in H&E staining. Furthermore, DAC + DOX@FPSD NP treatment could promote pyroptosis-associated antitumor immunity, as evidenced by the increased presence of CD3 + , CD4 + , and CD8 + T cells, heightened secretion of tumor necrosis factor-α and interferon-γ, elevated high-mobility group box-1 levels, and enhanced calreticulin exposure. The FPSD nanocarrier developed in this study had favorable stability, active targeting ability, biocompatibility, and controlled release properties, and the DAC + DOX@FPSD NPs represented an approach to antitumor therapy by inducing pyroptosis, which offers a promising avenue for breast cancer treatment.

The supramolecular palladium complex G-Pd, formed via self-assembly of the Pd-complex of guanidinium pillar[5]arene with Pd 2+ , was used to encapsulate doxorubicin to form G-Pd@DOX. The nanoparticles exhibit responsiveness to glutathione, controlled drug release, the ability to damage mitochondria, and potent anticancer activity while maintaining low toxicity towards normal cells. This work provides a good example for the application of pillararene-based palladium complexes in cancer therapy and is significant for the discovery of new medicines from supramolecular coordination complexes.