MAPK-Targeted Drug Delivered by a pH-Sensitive MSNP Nanocarrier Synergizes with PD-1 Blockade in Melanoma without T-Cell Suppression

The combination of BRAF/MEK-targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK-inhibitor-induced T-cell toxicity impedes effective cooperation. In this experiment, a pH-responsive on-demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein-isothiocyanate-loaded MSNP can be specifically delivered into tumor cells rather than T-cells. MEK-inhibitor-loaded MSNP avoids proliferative and functional inhibitions of T-cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK-inhibitor-induced suppression of activated CD8 + T-cells, and enhances the secretion of INF-γ and IL-2. The combination of BRAF inhibitor plus MSNP-loaded MEK inhibitor and anti-PD-1 antibody synergistically inhibits tumor growth via promoting robust immune-related antitumor response. This work provides a novel and generalized framework for combining T-cell-impaired targeted therapy and immune checkpoint blockade by using a nanoparticle-based delivery system.