mRNA Vaccine Platforms and Lipid Nanoparticle Delivery Systems: Molecular Advances, Clinical Breakthroughs, and Regulatory Perspectives (2020–2025)

Background: The success of mRNA vaccines against COVID-19 has catalyzed a paradigm shift in vaccinology. Messenger RNA (mRNA)-based platforms offer exceptional design flexibility, rapid manufacturing, and antigen-agnostic modularity, yet their full translational potential — spanning infectious disease prophylaxis, personalized cancer immunotherapy, and regulatory implementation in low- and middle-income countries — remains incompletely synthesized from a regulatory science perspective. Main body: This systematic review, conducted in accordance with PRISMA 2020 guidelines across PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov (January 2020–February 2025), synthesizes 68 peer-reviewed studies on four thematic pillars: (1) mRNA platform biology and engineering; (2) lipid nanoparticle (LNP) formulation and targeted delivery; (3) clinical-stage mRNA vaccines for HIV, RSV, influenza, CMV, and emerging pathogens; and (4) personalized cancer vaccines. Key findings include: the individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab demonstrated a 44% reduction in recurrence or death in resected melanoma (KEYNOTE-942, Phase IIb); mRNA-1345 (mRESVIA) achieved 83.7% efficacy against RSV lower respiratory tract disease and received EMA approval in June 2024; eOD-GT8 60mer induced HIV broadly neutralizing antibody precursors in 97% of Phase I participants; and next-generation selective organ-targeting (SORT) LNPs now enable tissue-specific mRNA delivery beyond hepatic default. Critically, this review — authored by scientists at Indonesia’s BPOM, one of the largest NMRAs among LMICs — is the first to systematically integrate regulatory science into an mRNA vaccine evidence synthesis, evaluating approval pathways, cold-chain constraints, pharmacovigilance requirements, and equitable access challenges from the standpoint of an LMIC NMRA: a dimension entirely absent from all five most recent systematic reviews in this field. Conclusion: mRNA-LNP technology represents a transformative and versatile vaccine platform with proven efficacy across oncology and infectious disease. Realizing its full global potential demands coordinated advances in thermostable formulation, manufacturing scalability, and fit-for-purpose regulatory frameworks in LMICs. The evidence synthesized here provides a molecular and regulatory roadmap for the next generation of mRNA vaccine development and approval through 2030.