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[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] 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]

Though much progress in utilizing tissue engineering technology to investigate tumor development in vitro has been made, the effective management of human melanoma is still a challenge in clinic due to lack of suitable 3D culture systems. In this study, we prepared a poly(γ-benzyl- l -glutamate)/poly(lactic acid) (PBLG/PLA) nanofiber membrane by electrospinning and demonstrated its suitability as a matrix for 3D culture of melanoma cells in vitro . The electrospun PBLG/PLA nanofiber membrane displayed a smooth and uniform fibrous morphology and had a desirable water contact angle of 79.3 ± 0.6°. The average diameter of PBLG/PLA nanofibers was 320.3 ± 95.1 nm that was less than that (516.2 ± 163.3 nm) of pure PLA nanofibers. The addition of PBLG into PLA decreased the cold crystallization peak of PLA fibers from 93 to 75 °C. The in vitro biocompatibility of PBLG/PLA nanofiber membrane was evaluated with B16F10 cells using PLA nanofiber membrane as control. It was found that, compared to PLA nanofiber membrane, PBLG/PLA nanofiber membrane could better support cell viability and proliferation, as indicated by MTT assay and live-dead staining. SEM results revealed that PBLG/PLA rather than PLA nanofiber membrane promoted the generation of tumoroid-like structures. These findings clearly demonstrated that the electrospun PBLG/PLA nanofiber membrane could mimick the extracellular matrix of melanoma microenvironment and be a promising platform for 3D cell culture. [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]