Xueliang Liu, Yuqing Li, Xinfeng Dai, Zhicheng Huang, Jiabei Li, Chuhuang Dong, Ziliang Dong, Dali Wei, Huayuan Zhou, Zhuang Liu, Yu Yang, Weihong Tan
Abstract mRNA vaccines hold remarkable promise for cancer immunotherapy, yet current nanoparticle systems face challenges in efficacy, dendritic cell (DC) targeting, and safety. Herein, we report a nanoplatform, Manganese‐Coordinated Polyvalent Aptameric System (COMPASS), enabling targeted co‐delivery of mRNA and Mn 2 + to lymph node dendritic cells (DC) to boost potent antitumor immunity. The COMPASS employed rolling circle amplification to generate single‐stranded DNA scaffolds with multivalent DC‐targeting aptamers and polyT domains, enabling stable mRNA hybridization via A‐T pairing. Various metal ions were screened, and Mn 2 + was found to enhance mRNA endosomal escape and activate the STING pathway in DCs, promoting their maturation and antigen presentation. Controlled nanoparticle size (∼200 nm) and aptamer‐mediated DC targeting markedly enhanced lymphatic accumulation. In vivo evaluations revealed that COMPASS achieved potent prophylactic and therapeutic antitumor efficacy comparable to commercial LNPs (e.g., SM‐102), while exhibiting significantly enhanced safety profiles. Importantly, lyophilized COMPASS formulations retained their structural integrity and bioactivity for at least three months at room temperature. Overall, COMPASS represents a promising next‐generation nanoplatform with significant translational potential for safe and effective cancer immunotherapy.