Jinchao Yu, Xinyan Li, Junyao Li, Nan Sun, Peng Cheng, Jiayi Huang, Sai Li, Rui Kuai
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引用次数: 0
Abstract
Activating the STING pathway in the cytosol of tumor-infiltrating antigen-presenting cells (APCs) represents a promising strategy to elicit potent antitumor immune responses for cancer therapy. However, STING agonists are mostly small hydrophilic molecules that suffer from rapid clearance and poor cytosolic delivery following systemic administration. While various nanoparticles have been developed to promote cytosolic delivery, they often exhibit premature drug release during circulation. Alternatively, stable nanoparticles with sustained release during circulation have poor cytosolic delivery. In this study, we have developed physically cross-linked hyaluronic acid (HA) and lipid hybrid nanoparticles containing cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), denoted as HLHC, to address these challenges. The HLH delivery system has sustained drug release due to multiple lipid layers physically cross-linked by HA. HLHC efficiently delivers cGAMP to the cytosol of APCs, inducing more IFNβ than cGAMP and liposomal cGAMP. HLH also improves the drug circulation time and biodistribution to the tumor compared with the liposomal formulation and free drug. Strikingly, a single dose of HLHC, but not liposomal cGAMP or free cGAMP, elicits potent antitumor immunity and regresses established MC38 tumors. A single dose of HLHC even regresses established B16F10 tumors upon combination with αPD-L1. Moreover, cured animals were protected from rechallenge with the same tumor cells. HLHC represents an efficient strategy to address delivery challenges associated with STING agonists and may have broad applications for the delivery of drugs acting in the cytosol.
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.