Background Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear “cold” tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response. Methods In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological. Results Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment. Conclusion The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune “cold” 4T1 into “hot” tumors.

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Hepatoma is a serious public health concern. New attempts are urgently needed to solve this problem. Melittin, a host defense peptide derived from the venom of honeybees, has noteworthy hemolysis and non-specific cytotoxicity in clinical applications. Here, the self-assembly of melittin and vitamin E-succinic acid-(glutamate)12 (VG) was fabricated via noncovalent π-stacking and hydrogen bonding interactions by an environment-friendly method without the use of “toxic” solvents. As expected, the designed self-assembly (denoted as M/VG nanoparticles) exhibits a uniform morphology with a particle size of approximately 60 nm and a zeta potential of approximately − 26.8 mV. Furthermore, added VG significantly decreased hemolytic activity, increased tumor-targeted effects, promoted the cellular uptake, and accelerate apoptosis. Our research provides a promising strategy for the development of natural self-assembled biological peptides for clinical application, particularly for transforming toxic peptides into safe therapeutic systems.