Enhanced Intratumoral Delivery of Immunomodulator Monophosphoryl Lipid A through Hyperbranched Polyglycerol-Coated...

Immunomodulatory agents have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting owing to poor pharmacokinetics and toxicity associated with systemic administration. Conversely, when locally delivered, immunomodulatory agents require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol-coated biodegradable nanoparticles (NPs) engineered for gradual drug release from the NP core, resulting in a more persistent stimulation of antitumor immune responses while minimizing systemic side effects. In a model of malignant melanoma, we demonstrate that hyperbranched polyglycerol-NP encapsulation significantly improves the antitumor efficacy of MPLA by enhancing its ability to remodel the tumor microenvironment. Relative to free MPLA, hyperbranched polyglycerol-coated NP-encapsulated MPLA significantly increased the NK cell- and cytotoxic T-cell-mediated antitumor immune response and tuned the tumor-draining lymph nodes toward a T helper 1 response. Furthermore, when combined with local delivery of a chemotherapeutic agent, hyperbranched polyglycerol-NP-MPLA induces the conversion of an immunosuppressive tumor microenvironment to immunogenic tumor microenvironment and significantly improves survival.