Engineered Lipid Nanoparticles beyond mRNA Vaccines: Advances in Lipid Design, Protein Corona Dynamics, and Expanding Therapeutic Horizons

Abstract

Engineered lipid nanoparticles (LNPs) have emerged as transformative delivery vehicles for nucleic acid‐based therapeutics, propelled into global prominence by the success of COVID‐19 mRNA vaccines. This review consolidates advances in LNP science over the period 2019–2026 with a focus on three interrelated pillars: (i) innovations in lipid design, encompassing novel ionizable lipid architectures, biodegradable linkers, PEGylation alternatives, and artificial intelligence (AI)‐driven formulation optimization; (ii) lipid metabolism and protein corona dynamics that govern biodistribution, immune recognition, and nanoparticle clearance; and (iii) expanding therapeutic applications beyond prophylactic vaccination, including CRISPR‐Cas9 gene editing, cancer immunotherapy, siRNA therapeutics, rare disease treatment, and central nervous system delivery. The novelty of this review lies in its integrative, regulatory‐science perspective—grounded in the mandate of a national medicines authority (Indonesia BPOM)—linking molecular lipid design to manufacturing scalability, long‐term safety, and equitable access. Critical knowledge gaps including robust extrahepatic targeting, standardized protein corona characterization, and regulatory harmonization are identified and evidence‐based future directions proposed. This synthesis aims to guide formulation scientists, clinician‐scientists, and regulatory professionals in advancing the next generation of LNP‐based precision nanomedicines.