PROTAC工程化蛋白/DNA纳米抗原是癌症免疫治疗中树突状细胞疫苗的强效增强剂。

Abstract

The efficacy of dendritic cell (DC) vaccines in cancer immunotherapy is often limited by weak immunogenicity due to inefficient antigen cross‐presentation (XPT). We previously combined a calcium carbonate (CaCO 3 ) delivery system with a proteolysis‐targeting chimera (PROTAC) to enhance antigen degradation. Along this line, we developed a protein/DNA‐integrated nanoantigen platform (HpOAC) co‐loading CaCO 3 with a His‐tagged ovalbumin (O) modified with the von Hippel‐Lindau (VHL) E3 ligase‐recruiting peptide ALAPYIP (HOA) and a eukaryotic plasmid encoding O‐ALAPYIP (pOA). HpOAC promoted DC maturation and migration via Ca 2+ release. Mechanistically, HOA provided an immediate antigen source, while pOA enabled sustained expression; both underwent ALAPYIP‐mediated VHL recruitment, enhancing O ubiquitination and proteasomal degradation, thereby amplifying XPT. Consequently, HpOAC‐DCs induced strong OT‐I/OT‐II T cell proliferation in vitro. In vivo, a single immunization with HpOAC‐DCs significantly suppressed tumor growth and elicited durable antigen‐specific T helper type 1 and cytotoxic T lymphocyte responses, outperforming single‐antigen vaccines. Under a two‐dose regimen, its anti‐tumor efficacy was improved compared to non‐PROTAC and in situ antigen vaccines. Thus, we constructed a PROTAC‐enhanced, protein/DNA‐integrated DC vaccine platform that synergizes immediate and sustained antigen supply with Ca 2+ ‐mediated adjuvanticity, offering a highly promising strategy for novel DC vaccine design. A PROTAC‐functionalized protein/DNA‐integrated nanoantigen platform is developed to enhance dendritic cell vaccine potency. By combining a VHL‐recruiting peptide‐modified antigen with a sustained expression plasmid within CaCO 3 nanoparticles, this system amplifies cross‐presentation, promotes DC maturation, and elicits robust Th1 and CTL responses, offering a promising strategy for cancer immunotherapy.