Intelligent bioinspired nanovesicles for controllable immune microenvironment reprogramming of drug-resistant breast cancer treatment

Abstract The immunosuppressive tumor microenvironment (TME) plays a critical role in the exacerbation of chemotherapy-induced multidrug resistance (MDR). To overcome MDR, a natural nanovesicle-based biomimetic nanosystem was created using low-frequency vibrational magnetic fields (VMF) and an 808 nm laser to help overcome drug resistance in tumors. This advanced platform integrates M1 macrophage-derived exosomes (M1-EXO) with magnetic nanoparticles, Ce6 labeled antisense oligonucleotides of heat shock protein 70 (HSP-70) and doxorubicin. This approach enables a triple-modality synergistic therapy that integrates immunotherapy, gene therapy, and enhanced photothermal therapy (PTT). Specifically, M1-EXO effectively reprogram tumor-associated M2 macrophages (TAMs) toward the antitumor M1 phenotype, while Ce6-mediated photodynamic therapy (PDT) amplifies reactive oxygen species (ROS)-dependent M1 repolarization. Further, the nanovesicles target HSP70 to suppress heat shock protein expression, thereby overcoming the thermal resistance of tumor cells and enhancing PTT. Concurrently, nanovesicles' favorable magnetic responsiveness enables direct destruction of cancer cells under VMF exposure, which greatly contributed to immunogenic cell death (ICD) activation. Consequently, this synergistic strategy initiates antitumor immunity and activates cytotoxic T lymphocytes. Both in vitro and in vivo studies demonstrate that this biomimetic nanovesicle reduces the half-maximal inhibitory concentration (IC50) of doxorubicin-resistant breast cancer cells by 96-fold. In conclusion, this nanoplatform successfully tackles drug resistance by actively targeting pathways that activate the immune system, and promotes exosomes from human peripheral blood mononuclear cells for transplantation immunotherapy in the future.