Functionalized Spiky Microcarriers Orchestrate STING Activation and Durable Antitumor Immunity

Abstract

The stimulator of interferon (IFN) genes (STING) pathway has garnered considerable attention due to its significant potential in anti-cancer effect. However, cyclic dinucleotides (CDNs), which are natural agonists or their derivatives for STING, are often hindered by their inherent properties of poor transmembrane permeability and potential systemic toxicity. Herein, we employed polyethylenimine (PEI)-functionalized spiky TiO₂ microparticles (SP-PEI) for the efficient delivery of CDNs into antigen-presenting cells (APCs). This delivery system leverages the electrostatic interaction between PEI and CDNs, allowing for the absorption of CDNs onto the spiky microparticle (SP) structure. Furthermore, the optimized microstructure of SP-PEI facilitates preferential phagocytosis by APCs, thereby enabling effective intracellular delivery of CDNs. Our findings demonstrated that SP-PEI significantly promoted CDNs phagocytosis by dendritic cells (DCs), leading to robust activation of the STING pathway and subsequent induction of type I interferons, which in turn fostered DC maturation. Furthermore, in MC38 tumor models, SP-PEI-CDN was observed to significantly delay the progression of both primary and distant tumors. Finally, the co-administration of SP-PEI-CDN with the chemotherapeutic agent doxorubicin (DOX) achieved excellent therapeutic efficacy against melanoma in both primary and distant tumor sites, underscoring the broad effectiveness of our delivery strategy.