Exploring a rational delivery system of integrating chemotherapy with immunotherapy to broaden benefits of cancer immunochemotherapy is still under challenge. Herein, we developed doxorubicin (DOX)-loaded biomimetic hybrid nanovesicles (DOX@LINV) via fusing artificial liposomes (LIPs) with tumor-derived nanovesicles (TNVs) for combinational immunochemotherapy. DOX@LINV with a homologous targeting ability could deliver DOX to tumor tissue and elicit an effective immunogenic cell death response to improve the immunogenicity of a tumor. Meanwhile, the preserved tumor antigens and endogenous danger signals in DOX@LINV activated dendritic cells and induced a subsequent antigen-specific T cell immune response. DOX@LINV displayed a specific antitumor effect on murine melanoma, Lewis lung cancer, and 4T1 breast cancer based on the infiltration of effector immune cells and improvement of the immunosuppressive tumor microenvironment. Furthermore, the combination of DOX@LINV with immune checkpoint inhibitor amplified antitumor efficacy with 33.3% of the mice being tumor-free. Therefore, the hybrid LINV is a promising drug delivery platform with a boosted antitumor immune response for effective immunochemotherapy.

Blocking immune checkpoints with monoclonal antibody has been verified to achieve potential clinical successes for cancer immunotherapy. However, its application has been impeded by the “cold” tumor microenvironment. Here, weak acidity-responsive nanoparticles co-loaded with CRISPR/Cas9 and paclitaxel (PTX) with the ability to convert “cold” tumor into “hot” tumor are reported. The nanoparticles exhibited high cargo packaging capacity, superior transfection efficiency, well biocompatibility, and effective tumor accumulation. The CRISPR/Cas9 encapsulated in nanoparticles could specifically knock out cyclin-dependent kinase 5 gene to significantly attenuate the expression of programmed death-ligand 1 on tumor cells. More importantly, PTX co-delivered in nanoparticles could significantly induce immunogenic cell death, reduce regulatory T lymphocytes, repolarize tumor-associated macrophages, and enhance antitumor immunity. Therefore, the nanoparticles could effectively convert cold tumor into hot tumor, achieve effective tumor growth inhibition, and prolong overall survival from 16 to 36 days. This research provided a referable strategy for the development of combinatorial immunotherapy and chemotherapy.

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Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/ PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a smallmolecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.

In the treatment of malignant tumors, the combination of chemotherapy that can directly kill tumor cells and immunotherapy that can activate the body's immune system and regulate tumor microenvironments is becoming one of the most promising cancer treatments. However, to co-deliver agents with different physicochemical properties for immunochemotherapy is still facing a challenge. Here, nanoparticles are developed for the co-delivery of the hydrophobic chemotherapeutic drug paclitaxel (PTX) and biomacromolecule interleukin-12 (IL-12) through the acid-sensitive material mPEG-Dlink m -PDLLA and low-temperature expansion effect of Pluronic F127. The nanoparticles encrich in the tumor site, significantly inhibit the growth and metastasis of breast cancer cells 4T1, and prolong the overall survival of tumor-bearing mice. The underlying immune mechanism is further explored. The combination of PTX and IL-12 activates T lymphocytes and NK cells to release IFN-, selectively inhibits regulatory T cells and induces M1-type differentiation of tumor-related macrophages, thereby improving tumorimmunosuppressive microenvironments. This study may provide an effective strategy for cancer immunochemotherapy through co-delivery of chemotherapeutic drug and immune cytokine by the facile thermo-sponge nanoparticles.

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(HUST) for performing rheological test and polarized optical microscopy. The authors also thank Tongji Medical College of HUST for CLSM and FACS analysis. Finally, I would like to thank my husband Ping Li for his support all the way.