Targeted delivery of pexidartinib to tumor-associated macrophages via legumain-sensitive dual-coating nanoparticles for cancer immunotherapy.

Tumor-associated macrophage (TAM) is regarded as an appealing cell target for cancer immunotherapy. However, it remains challenging to selectively eliminate M2-like TAM in tumor microenvironment. In this work, we employed a legumain-sensitive dual-coating nanosystem (s-T-NPs) to deliver CSF-1R inhibitor pexidartinib (PLX3397) for targeting TAM therapy. The PLX3397-loaded NPs exhibited uniform size of ∼240 nm in diameter, good drug loading capacity and efficiency, as well as sustained drug release profile. Compared to non-sensitive counterpart ns-T-NPs, s-T-NPs showed distinguished selectivity upon M1 and M2 macrophage uptake with relation to incubation time and dose. Besides, the selectivity of anti-proliferation effect was also identified for s-T-NPs against M1 and M2 macrophage. In vivo imaging demonstrated that s-T-NPs exhibited much higher tumoral accumulation and TAM recognition specificity as compared to non-sensitive ns-T-NPs. In vivo efficacy verified that s-T-NPs formulation was much more effective than ns-T-NPs and other PLX3397 formulations to treat B16F10 melanoma via targeting TAM depletion and modulating tumor immune microenvironment. Overall, this study provides a robust and promising nanomedicine strategy for TAM-targeted cancer immunotherapy.