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• 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]