In situ reprogramming of tumor associated macrophages with versatile nano-epigenetic inhibitor for lung cancer therapy.

Lung cancer remains the most common cause of cancer-related deaths globally. Although immunotherapy has become a promising approach for the treatment of lung cancer, it is hindered by T cell exhaustion due to the unfavorable tumor microenvironment (TME). The in situ reprogramming of tumor-associated macrophage (TAM) has shown a powerful effect on lung cancer therapy. However, the present approaches showed difficulty in realizing effective TAM reprogramming due to the low efficiency or complicated operation. In this study, we developed a versatile nano-epigenetic inhibitor (CREDIT), constructed using biodegradable polymer Poly(lactic-co-glycolic acid) grafted with histidine (PLGA-his) to load the epigenetic inhibitor TMP195. The nanoparticles were further modified with red blood cell membranes (RBCM) that conjugated with a TAM targeting peptide, namely CRV. CREDIT showed enhanced specificity both in vitro and in vivo, and also induced improved cumulative drug release in acidic environments. CREDIT also led to the in situ reprogramming of M2 TAM into the M1 phenotype, which remodeled the TME into an immune-responsive one with an increased number of T cells and a decreased number of myeloid-derived suppressor cells (MDSCs) in the tumor. Based on the macrophage-targeting immunotherapy, CREDIT inhibited the growth of the tumor by approximately one-fifteenth compared with the control group in both subcutaneous and orthotopic tumor-bearing mice. The versatile nano-epigenetic inhibitor showed effective in situ reprogramming of TAM, which may serve as a novel therapeutic strategy for treating lung cancer.