FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy

FAP-C NPs, consisting of PLGA-C NPs encapsulated with the vitamin D analog calcipotriol as the core and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and restore the activated CAFs to a quiescent state to remodel the tumor microenvironment and improve the sensitivity to radiotherapy. [Display omitted] Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core–shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index