Biomimetic Nanoplatform for Dual‐Targeted Clearance of Activated and Senescent Cancer‐Associated Fibroblasts to Improve Radiation Resistance in Breast Cancer

Abstract Radiation resistance in breast cancer resulting in residual lesions or recurrence is a significant cause to radiotherapy failure. Cancer‐associated fibroblasts (CAFs) and radiotherapy‐induced senescent CAFs can further lead to radiation resistance and tumor immunosuppressive microenvironment. Here, an engineering cancer‐cell‐biomimetic nanoplatform is constructed for dual‐targeted clearance of CAFs as well as senescent CAFs. The nanoplatform is prepared by 4T1 cell membrane vesicles chimerized with FAP single‐chain fragment variable as the biomimetic shell for targeting of CAFs and senescent CAFs, and PLGA nanoparticles (NPs) co‐encapsulated with nintedanib and ABT‐263 as the core for clearance of CAFs and senescent CAFs, which are noted as FAP‐CAR‐CM@PLGA‐AB NPs. It is evidenced that FAP‐CAR‐CM@PLGA‐AB NPs directly suppressed the tumor‐promoting effect of senescent CAFs. It also exhibits prolonged blood circulation and enhanced tumor accumulation, dual‐cleared CAFs and senescent CAFs, improved radiation resistance in both acquired and patient‐derived radioresistant tumor cells, and effective antitumor effect with the tumor suppression rate of 86.7%. In addition, FAP‐CAR‐CM@PLGA‐AB NPs reverse the tumor immunosuppressive microenvironment and enhance systemic antitumor immunity. The biomimetic system for dual‐targeted clearance of CAFs and senescent CAFs provides a potential strategy for enhancing the radio‐sensitization of breast cancer.