Progress and Prospects of Nanodelivery Systems in Metabolism-Regulated mRNA Vaccines.

mRNA vaccines face two major challenges in tumor immunotherapy: inefficient delivery and an immunosuppressive tumor microenvironment (TME) driven by metabolic reprogramming. This review proposes that nanodelivery systems can overcome both obstacles by protecting and targeting mRNA while simultaneously reshaping tumor metabolism and immunity. We summarize how nanocarriers act as "metabolism-immunity dual regulation centers" through three mechanisms: co-delivery of metabolic regulators, intrinsic modulation of immune cell metabolism via material properties, and TME-responsive spatiotemporal release. We further emphasize the central roles of the mTOR/STAT3/HIF-1α signaling axes in linking metabolic dysregulation to immune suppression and compare the metabolic adaptability of major nanocarrier platforms. Finally, we discuss rational design principles, validation strategies, clinical translation barriers, and future directions, including AI-assisted design and engineered live carriers. This review provides an integrated framework for developing next-generation antitumor mRNA vaccines. The proposed "metabolism-immunity dual regulation" strategy combines efficient delivery, metabolic reprogramming, and durable immune activation.