mRNA-LNP vaccines: rational design, delivery optimization, and clinical translation

Abstract

Messenger RNA (mRNA) vaccines face core challenges including low-delivery efficiency and immunogenicity, limiting their wide-ranging applications in infectious disease prevention and cancer therapy. Lipid nanoparticles (LNPs), the most clinically validated non-viral delivery platform, address these challenges by encapsulating and protecting mRNA, promoting cellular uptake, and mediating endosomal escape. mRNA-LNP vaccines leverage a “rapid design + flexible production” advantage, decisively demonstrated by the success of COVID-19 vaccines such as BNT162b2. This review systematically analyzes mRNA-LNP vaccine development, focusing on core optimization strategies: (1) mRNA sequence engineering (nucleoside modification and UTR/poly(A) tail optimization) to enhance stability and translation efficiency; (2) LNP formulation (component ratio optimization, SPOT strategies, etc.) to modulate immune responses and enable organ targeting; and (3) LNP surface functionalization (with small molecules, peptides, and antibodies) for precise specific cell or organ targeting. Although multiple candidate vaccines for infectious disease prevention and cancer treatment have entered clinical trials, their clinical translation is still limited by insufficient targeting accuracy, potential immunogenicity and toxicity, and the challenge of universal delivery systems. Future breakthroughs require the integration of multidisciplinary innovations, focusing on the development of degradable lipids and novel targeting ligands to improve delivery precision, the application of more biocompatible polymers (such as pSar and POx) to replace PEG to enhance safety, and the use of artificial intelligence (AI) to accelerate LNP formulation design and performance prediction. This review summarizes the key optimization strategies and clinical progress and explores future directions to overcome the existing bottlenecks and promote mRNA-LNP technology as the cornerstone of next-generation precision medicine.