Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti–programmed death 1 (α-PD1) or anti–programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4
+
and CD8
+
T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.
Cytosolic delivery of small interfering RNA (siRNA) remains challenging, and a profound understanding of the cellular uptake and intracellular processing of siRNA delivery systems could greatly improve the development of siRNA-based therapeutics. Here, we show that caveolaemediated endocytosis (CvME) accounts for the robust siRNA delivery of mannose-modified trimethyl chitosan-cysteine/ tripolyphosphate nanoparticles (MTC/TPP NPs) to macrophages by circumventing lysosomes. We show that the Golgi complex and ER are key organelles required for the efficient delivery of siRNA to macrophages in which the siRNA accumulation positively correlates with its silencing efficiency (r = 0.94). We also identify syntaxin6 and Niemann−Pick type C1 (NPC1) as indispensable regulators for MTC/TPP NPs-delivered siRNA into macrophages both in vitro and in vivo. Syntaxin6 and NPC1 knockout substantially decrease the cellular uptake and gene silencing of the siRNA delivered in MTC/ TPP NPs in macrophages, which result in poor therapeutic outcomes for mice bearing acute hepatic injury. Our results suggest that highly efficient siRNA delivery can be achieved via CvME, which would give ideas for designing optimal delivery vectors to facilitate the clinical translation of siRNA drugs.
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