Personalized neoantigen mRNA vaccines for pancreatic cancer: the role of lipid nanoparticle delivery systems.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by late diagnosis, frequent recurrence, limited treatment options, and an immunosuppressive tumor microenvironment. These features have encouraged the development of personalized approaches targeting tumor-specific neoantigens.

Objective: This review discusses the development and therapeutic potential of personalized neoantigen mRNA vaccines for PDAC, with particular emphasis on lipid nanoparticle (LNP) delivery systems and their role in shaping antitumor immunity.

Methods: Published literature on PDAC, neoantigen identification, personalized cancer vaccines, mRNA engineering, and LNP-based delivery was reviewed and synthesized, with emphasis on preclinical findings, clinical evidence, and translational challenges.

Results: Advances in sequencing and computational approaches have improved the identification of patient-specific neoantigens, while mRNA platforms allow multiple neoantigens to be encoded in a flexible vaccine format. LNPs provide protection and efficient intracellular delivery of mRNA and can also influence antigen-presenting cell activation, inflammatory signaling, and T-cell responses. Preclinical studies have demonstrated neoantigen-specific immunity and improved tumor control in PDAC models. Early clinical studies of autogene cevumeran showed measurable vaccine-induced T-cell responses, with an association between stronger immune responses and longer recurrence-free survival. However, these findings remain preliminary because of small study populations and the absence of randomized controls. Tumor heterogeneity, immunosuppression, neoantigen prediction, manufacturing complexity, cost, and delivery barriers remain important challenges.

Conclusion: Personalized neoantigen mRNA vaccines delivered through LNPs represent a promising investigational strategy for PDAC. Further advances in neoantigen selection, mRNA engineering, LNP optimization, targeted delivery, and clinical evaluation are needed to establish their safety, efficacy, and therapeutic role.