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[Display omitted] Copper-based nanomaterials show considerable potential in the chemodynamic therapy of cancers. However, their clinical application is restricted by low catalytic activity in tumor microenvironment and copper-induced tumor angiogenesis. Herein, a novel copper-doxorubicin-anlotinib (CDA) nanoconjugate was constructed by the combination of copper-hydrazide coordination, hydrazone linkage and Schiff base bond. The CDA nanoconjugate consists of a copper-3,3′-dithiobis(propionohydrazide)-doxorubicin core and an anlotinib-hyaluronan shell. Benefiting from hyaluronan camouflage and abundant disulfide bonds and Cu2+, the CDA nanoconjugate possessed excellent tumor-targeting and glutathione-depleting abilities and enhanced chemodynamic efficacy. Released doxorubicin significantly improved copper-mediated chemodynamic therapy by upregulating nicotinamide adenine dinucleotide phosphate oxidase 4 expression to increase intracellular H 2 O 2 level. Furthermore, the nanoconjugate produced excessive •OH to induce lipid peroxidation and mitochondrial dysfunction, thus greatly elevating doxorubicin-mediated chemotherapy. Importantly, anlotinib effectively inhibited the angiogenic potential of copper ions. In a word, the CDA nanoconjugate is successfully constructed by combined coordination and pH-responsive linkages, and displays the great potential of copper-drug conjugate for targeted synergistic chemo/chemodynamic/antiangiogenic triple therapy against cancers. [ABSTRACT FROM AUTHOR]

Immunotherapy shows great promise in the treatment of hepatocellular carcinoma (HCC), however, the low response rate of HCC patients to immunotherapy caused by inadequately immunogenic and immunosuppressive tumor microenvironment (TME) is a huge challenge. Herein, a donut‐like multifunctional polysaccharide nanoplatform (GH‐PID) is constructed from doxorubicin/aldehyde hyaluronan nanoring, indocyanine green/hydroxyethyl chitosan nanocomplex, and HCC‐bitargeted galactosamine‐hyaluronan conjugate via a facile self‐assembly process. The GH‐PID nanodonuts exhibit excellent HCC‐targeted ability and synergetic photochemotherapy effect with a coefficient index of about 0.44. Moreover, near infrared laser‐irradiated GH‐PID nanodonuts show robust therapeutic efficacy in HCC mouse models by virtue of photochemotherapy‐augmented immunogenic cell death (ICD) effect. The remarkable ICD in combination with programmed death‐1 antibody efficiently eradicates primary tumors and inhibits distant tumor growth and lung metastasis of HCC by maturing dendritic cells, increasing CD8+ T cell infiltration, suppressing the expansion and trafficking of immunosuppressive myeloid‐derived suppressor cells, and ameliorating immunosuppressive TME. This study provides a facile and versatile strategy to construct polysaccharide nanodonuts integrating multifunctionality and highly efficient HCC‐targeted ability, and the nanodonuts‐based ICD inducer holds great promise for potentiating systemic antitumor immunity and programmed death‐1/programmed death‐ligand 1 blockade efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H 2 O 2 to O 2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment. [ABSTRACT FROM AUTHOR]

[Display omitted] Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO 2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H 2 O 2 into O 2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O 2 -enhanced efficient topical dual-phototherapy of breast cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H 2 O 2 to O 2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment. [ABSTRACT FROM AUTHOR]

[Display omitted] Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO 2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H 2 O 2 into O 2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O 2 -enhanced efficient topical dual-phototherapy of breast cancer. [ABSTRACT FROM AUTHOR]

Cuproptosis is a very newly recognized regulated cell death modality that is distinct from known death mechanisms and shows enormous prospect in cancer treatment. However, its efficacy is copper‐dependent and restricted by strictly regulated copper metabolism. Herein, a novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) is developed as an oxidative stress amplifier and copper/iron metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF is fabricated from Cu2+, 3,3′‐dithiobis(propionohydrazide) and Fe3+ via an unsaturated coordination‐etching integration strategy, and then doxorubicin is loaded followed by surface decoration with hyaluronan. The obtained DOX@Fe/CuTH exhibits tumor microenvironment‐triggered catalytic therapeutic property, wherein it can amplify cellular oxidative stress by simultaneously boosting H2O2 production and depleting glutathione. Moreover, it can cause mitochondrial dysfunction and downregulate the expressions of copper transporter ATP7A and iron transporter FPN 1, thereby leading to metabolic disorders and high retentions of copper/iron in cytoplasm for •OH generation. The overloaded Cu2+ can cause lipoylated protein dihydrolipoamide S‐acetyltransferase aggregation and lead to cellular cuproptosis. Collectively, both augmented oxidative stress and overloaded copper/iron induce potent ferroptosis, which synergizes with cuproptosis and DOX‐mediated apoptosis to efficiently suppress tumor growth. This bimetallic hollow nanoplatform provides a new therapeutic modality paradigm to boost cuproptosis‐related therapies. [ABSTRACT FROM AUTHOR]

Polysaccharide hydrogels are promising candidate matrices for recapitulating the characteristics of extracellular matrix (ECM) in breast tumors in terms of their structure and composition. Herein, to obtain an ECM-mimetic matrix, hydroxyethyl chitosan (HECS) hydrogels were prepared through Schiff-base crosslinking reaction using dialdehyde hyaluronic acid as crosslinker. The obtained HECS hydrogels displayed a highly porous structure, a stiffness comparable to that of breast tissue, and a fast water-absorption speed. The amount of crosslinker had great effects on the swelling and rheological behaviors of the HECS hydrogels. Preliminary results from in vitro biological assessments confirmed that MCF-7 cells incubated within HECS hydrogels preferred to grow into three-dimensional spheroids. Importantly, the cells displayed enhanced migrative capability and upregulated expression levels of MMP-2, TGF-β and VEGF in comparison to two-dimension cultured cells. Hence, the HECS hydrogels show great promise as a biomimetic ECM in constructing breast tumor models. [ABSTRACT FROM AUTHOR]

• CIC-Gal nanomissiles were constructed by dual-coordination-driven self-assembly. • CIC-Gal nanomissiles showed prominent size/charge dual-transformability function. • CIC-Gal nanomissiles achieved synergistic chemotherapy/PDT/PTT in HCC. • CIC-Gal nanomissiles could induce ICD and promote CD8+ T cell infiltration into HCC. • CIC-Gal/αPD-1 combination activated robust systemic antitumor immunity in HCC. PD-1 blockade therapy holds great potential for curing hepatocellular carcinoma (HCC), but its efficacy is severely restrained by inefficient CD8+ T cells and abundant immunosuppressive myeloid-derived suppressor cells (MDSCs) in tumors. Moreover, the solid feature of HCC limits drugs' penetration depth. Herein, cisplatin/indocyanine green (ICG)-coloaded polysaccharide-based nanomissiles (CIC-Gal) with galactose-mediated tumor targeting ability and tumor microenvironment (TME)-responsive size/charge dual-transformability are constructed by coordination-driven self-assembly. The nanoparticles can efficiently accumulate in tumors and exert antitumor effects on HCC via combinational chemotherapy/phototherapy. Importantly, CIC-Gal nanoparticles may protect cisplatin from glutathione-mediated detoxification by depleting glutathione. Photodynamic therapy rather than photothermal therapy plays a predominant role in ICG-mediated phototherapy. Furthermore, CIC-Gal nanoparticles can induce prominent immunogenic cell death (ICD), promote dendritic cells maturation, and activate robust systemic antitumor immunity in combination with αPD-1, which efficiently eradicates primary tumors, inhibits distant tumor growth and lung metastasis, and prolongs survival of tumor-bearing mice by promoting CD8+ T cell infiltration in tumors, suppressing the expansion and trafficking of MDSCs, and reshaping immunostimulatory TME. Collectively, this study provides a drug-based coordination-driven polysaccharide nanomissile construction approach, and the CIC-Gal nanoparticles display a strong immunomicroenvironment-reeducating ability for potentiating HCC immunotherapy. [ABSTRACT FROM AUTHOR]

• A pioneering "grafting from" drug coordination polymerization strategy was proposed. • A fully-coordinated and full-active Cu 2 O/drug core/shell nanoplatform was prepared. • Obtained nanoplatform-mediated ROS storm could induce immunogenic cell death. • Nanoplatform/αPD-1 combination could induce robust systemic antitumor immunity. Precise manipulation of reactive oxygen species (ROS) breakthrough threshold exhibits great potential in destroying solid tumors, reprogramming "immune-cold" tumor and potentiating immunotherapy. However, it is still challenging to develop efficient ROS initiation devices. Herein, we propose a pioneering "grafting from" drug coordination polymerization strategy and develop a fully-coordinated and full-active Cu 2 O/drug core/shell nanoparticles for multimodal cancer therapy. Chemotherapeutic drug cisplatin (CDDP) and photosensitizer indocyanine green (ICG) were loaded onto the surface of hydrazided hyaluronic acid-decorated Cu 2 O (HA-Cu 2 O) nanoparticles through an infinite hydrazide-cisplatin-sulfonic acid coordination mechanism, obtaining CDDP/ICG-coloaded HA-Cu 2 O (HCCI) nanoplatform. The HCCI nanoplatform exhibited a rapid acid-responsive dissociation behavior and released ICG, Cu+ and CDDP to achieve efficient triple combined photodynamic therapy/chemodynamic therapy/chemotherapy. Importantly, such a combination induced efficient immunogenic cell death cascade mediated by powerful ROS storm to reprogram "immune-cold" tumors and potentiate immunotherapy. The combination of HCCI nanoplatform and αPD-1 not only eradicated primary tumors but effectively inhibited distal tumor growth, lung metastasis and tumor recurrence through reprogramming tumor microenvironment and activating CD8+ T cell antitumor immunity. Collectively, we have presented a drug coordination polymerization loading strategy to develop a robust multimodal antitumor nanoplatform, and this study provides a new direction for the design of nanodrug delivery systems. [ABSTRACT FROM AUTHOR]

A novel and all-active aMOF, DOX@FeTH, is developed via a one-step self-assembly strategy. The aMOF can effectively suppress tumor growth via a ferroptosis-apoptosis synergetic therapeutic modality. Moreover, the aMOF has excellent photothermal performance and the hyperthermia can enhance tumor penetration and further improve antitumor effect. Owing to simple ingredients, facile preparation process, and integrated multifunctionalities, DOX@FeTH aMOF holds great potential for clinical translation. [Display omitted] • A novel aMOF with triple-stimuli responsiveness was prepared via one-pot method. • The aMOF with favorable photothermal effect could penetrate deeply into tumor. • Self-supplied Fe2+, inactivated GPX4 and elevated H 2 O 2 co-induced ferroptosis. • The aMOF killed tumor cells via a ferroptosis-apoptosis synergistic modality. The combination of ferroptosis and apoptosis that act with different mechanisms holds enormous potential in cancer treatment. However, how to simply but effectively integrate the two modalities into a single platform is an enormous challenge. Herein, based on our newly discovered Fe(II)-hydrazide coordination self-assembly strategy, we design and develop an all-active amorphous metal organic framework (aMOF) for photothermally boosted ferroptosis-apoptosis synergistic anti-tumor therapy. The aMOF is prepared via one-pot co-assembly of doxorubicin (DOX), Fe2+ ions and 3,3′-dithiobis(propionohydrazide) (TPH) and subsequent decoration with TPH-functionalized hyaluronic acid. The obtained DOX@FeTH is amorphous in structure, and it exhibits favorable photothermal performance and displays pH/GSH/laser triple-responsive degradation behavior. The aMOF can be specifically internalized by CD44-overexpressed 4T1 cells and efficiently inhibit GPX4 activity via disulfide bond-mediated glutathione depletion, elevate intracellular H 2 O 2 level by DOX-induced NOX4 activation, and consequently amplify lipid peroxidation with the assistance of self-supplied Fe2+, resulting in remarkable ferroptotic cell death. Meanwhile, the released DOX causes apoptotic cell death. Moreover, the aMOF-mediated hyperthermia can promote tumor penetration and augment the synergistic efficacy. Hence, the tumors are effectively suppressed by the synergistic treatment of DOX@FeTH with laser. This work provides a new strategy for fabricating aMOFs and opens a new horizon for tumor treatment. [ABSTRACT FROM AUTHOR]

• Nanozyme-assisted PDT nanoplatform was prepared by an innovative dual coordination. • Obtained nanoplatform showed tri-enzyme activity to potentiate ROS generation efficacy. • Obtained nanoplatform-mediated ROS storm could induce immunogenic cell death. • Nanoplatform/αPD-1 combination could induce robust systemic antitumor immunity. Induction of immunogenic tumor cell death (ICD) is a promising strategy to potentiate immune checkpoint blockade (ICB) efficacy. However, it is still a huge challenge to develop efficient ICD-inducing nanomedicine. Herein, a copper nanozyme-assisted photodynamic therapy (PDT) nanoplatform nHACI was developed to achieve efficient ICD induction and robust systemic antitumor immune response through amplifying intracellular oxidative stress. The nHACI was fabricated from hydrazided hyaluronan and Cu2+ through an innovative hydrazide-copper coordination and in situ mineralization process, followed by loading of photosensitizer indocyanine green (ICG) via ICG-copper coordination. The nHACI exhibited superior drug loading efficiency, tumor microenvironment-responsive degradation behavior, and Fenton-like, glutathione oxidase-like and catalase-like triple activities. Importantly, it could not only deplete glutathione and concurrently generate 1O 2 and ·OH that amplified oxidative stress and induced ICD but also downregulate the proportion of M2 macrophages in tumors. The combination of nHACI-based PDT and PD-1 blockade could efficiently eradicate primary tumors, inhibit distant tumor growth and lung metastasis, and prevent tumor recurrence, demonstrating activation of robust systemic antitumor immune response. Collectively, this study presents a novel coordination assembly approach and nHACI holds great potential in eradicating primary tumors and potentiating ICB therapy via inducing ICD. [ABSTRACT FROM AUTHOR]

It is still a huge challenge for concurrent highly efficient loading of chemotherapeutic agent and photosensitizer into single nanocarrier via stimuli-responsive linkages due to their different physicochemical properties and pharmacokinetics. Herein, based on the discovery of unique cisplatin-hydrazide and cisplatin-indocyanine green (ICG) coordination reactions, a multifunctional coordination nanoprodrug, cisplatin/ICG co-loaded hydrazided hyaluronan/bovine serum albumin (HBCI) nanoparticles, was developed by a desolvation-dual coordination process. The nanoprodrug exhibited ultrahigh drug loading efficiency and glutathione/NIR light dual-responsive drug release behavior. In vitro cellular studies demonstrated efficient internalization and apoptosis-inducing ability of the nanoprodrug in HepG2 cells. In vivo results confirmed the efficacious tumor accumulation and biosafety of HBCI nanoprodrug and synergistic effect of HBCI-based combined photodynamic chemotherapy on inhibiting tumor growth. Overall, this work not only provides a novel dual coordination approach for highly efficient loading of cisplatin and ICG but also verifies the therapeutic potential of HBCI nanoprodrug in combating hepatocellular carcinoma. [Display omitted] [ABSTRACT FROM AUTHOR]

2D cell culture is widely utilized to develop anti-cancer drugs and to explore the mechanisms of cancer tumorigenesis and development. However, the findings obtained from 2D culture often fail to provide guidance for clinical tumor treatments since it cannot precisely replicate the features of real tumors. 3D tumor models capable of recapitulating native tumor microenvironments have been proved to be a promising alternative technique. Herein, we constructed a breast tumor model from novel hyaluronic acid (HA) hydrogel which was prepared through photocrosslinking of methacrylated HA. The hydrogel was used as a biomimetic extracellular matrix to incubate MCF-7 cells. It was found that methacrylation degree had great effects on hydrogel's microstructure, mechanical performances, and liquid-absorbing and degradation abilities. Optimized hydrogel exhibited highly porous morphology, high equilibrium swelling ratio, suitable mechanical properties, and hyaluronidase-responsive degradation behavior. The results demonstrated that the HA hydrogel facilitated MCF-7 cell proliferation and growth in an aggregation manner. Furthermore, 3D-cultured MCF-7 cells not only up-regulated the expression of VEGF, bFGF and interleukin-8 but exhibited greater invasion and tumorigenesis capabilities compared with 2D-cultured cells. Therefore, the HA hydrogel is a reliable substitute for tumor model construction. [Display omitted] • The hyaluronic acid hydrogel was synthesized by a facile photo-crosslinking approach. • 3D breast tumor models were successfully constructed from hyaluronic acid hydrogels. • 3D-cultured MCF-7 cells efficiently replicated key cellular features of tumor in vivo. • 3D-cultured MCF-7 cells exhibited enhanced tumorigenicity than 2D-cultured ones. [ABSTRACT FROM AUTHOR]