mRNA lipid nanoparticle cancer vaccine platform delivering multiple STING activators for enhanced antitumor activity
(1) Zeng Y (2) Xu J (3) Wang J (4) Xue L (5) Liu J (6) Geisler HC (7) Ma X (8) Melamed JR (9) Shi Q (10) Padilla MS (11) Luo Z (12) Zhu J (13) Thatte AS (14) Figueroa-Espada CG (15) Ang MJY (16) Murray AM (17) Yamagata HM (18) Kim D (19) Metzloff AE (20) Weissman D (21) Mitchell MJ
Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.
Contributed by Paula Hochman
(1) Zeng Y (2) Xu J (3) Wang J (4) Xue L (5) Liu J (6) Geisler HC (7) Ma X (8) Melamed JR (9) Shi Q (10) Padilla MS (11) Luo Z (12) Zhu J (13) Thatte AS (14) Figueroa-Espada CG (15) Ang MJY (16) Murray AM (17) Yamagata HM (18) Kim D (19) Metzloff AE (20) Weissman D (21) Mitchell MJ
Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.
Contributed by Paula Hochman
ABSTRACT: mRNA-based cancer vaccines offer a modular and safe platform to elicit antitumor immunity, yet their efficacy is often limited by inefficient mRNA delivery and inadequate dendritic cell (DC) activation, both of which are essential for initiating robust cytotoxic T cell responses. Inadequate innate immune activation coupled with poor antigen presentation further diminishes their effectiveness, particularly in immunologically "cold" tumors. While stimulator of interferon genes (STING) agonists can enhance DC maturation and cross-presentation, their therapeutic utility is constrained by poor intracellular delivery and limited colocalization with tumor antigens. In this study, we developed a lipid nanoparticle (LNP) platform via high-throughput screening of ionizable lipids for potent mRNA delivery to DCs both in vitro and in vivo. To amplify immune activation, we coencapsulated the STING agonists c-di-AMP (AMP) and manganese (Mn(2+)) together with tumor antigen-encoding mRNA into the lead LNP formulation. This codelivery strategy synergistically activated type I interferon signaling, upregulated costimulatory molecules, enhanced antigen presentation, and elicited potent tumor-specific T cell responses and superior antitumor efficacy. Our results demonstrate that integrating innate immune stimulation with mRNA-LNP delivery provides a promising strategy to overcome current limitations in mRNA vaccine efficacy and to improve cancer immunotherapy outcomes.
Author Info:
(1) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (2) Department of Bioengineering, University of Pennsylvania, P
hiladelphia, PA 19104. ROR: https://ror.org/00b30xv10 (3) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (4) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (5) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (6) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (7) Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, China. ROR: https://ror.org/04f49ff35 (8) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (9) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (10) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (11) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (12) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (13) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (14) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (15) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Republic of Singapore, Singapore 138668, Singapore. ROR: https://ror.org/036wvzt09 (16) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (17) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (18) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (19) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (20) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (21) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10
Citation: Proc Natl Acad Sci U S A 2026 Jul 14 123:e2525718123 Epub07/08/2026
