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

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 < 0.2). The zeta potential of FAP-C NPs was -12.63 ± 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.