Charge convertible biomimetic micellar nanoparticles for enhanced melanoma-targeted therapy through tumor cells and tumor-associated macrophages dual chemotherapy with IDO immunotherapy

Immunotherapy is demonstrating great potential for cancer therapy nowadays. However, its therapeutic efficacy has been impeded by the natural biological barriers, poor immunogenicity, and highly immunosuppressive tumor microenvironment (ITM). In this study, a charge convertible biomimetic micellar nanoparticle co-encapsulated with chemotherapeutic drug paclitaxel (PTX) and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 is developed for combined chemoimmunotherapy. The resulting nanoparticle presents prolonged blood circulation as well as specific uptake in both B16F10 melanoma cells and M2-type tumor-associated macrophages (TAM2) via folate receptor-mediated endocytosis. Moreover, rapid drug release could be elegantly triggered by the charge conversion from negative to positive in response to the acidic environment in the lysosomes. PTX can lead to immunogenic cell death to provoke antitumor immunogenicity and intratumoral infiltration of effector T cells, while the ITM is reversed by simultaneous NLG919-mediated IDO inhibition and PTX-induced TAM2 elimination. Such a biomimetic nanomedicine efficiently boosts the synergistic antitumor treatment and minimizes systemic side effects in a mouse melanoma model. Hence, this strategy demonstrates high drug delivery efficiency and provides a potential application for the combined chemoimmunotherapy of melanoma.