LIPID-BASED NANOPARTICLE FORMULATION STRATEGIES FOR TARGETED DRUG, MRNA, AND GENE DELIVERY; A REVIEW

Abstract

Lipid-based nanoparticles have emerged as a transformative platform for precision medicine, enabling the targeted delivery of diverse therapeutic payloads including small molecule drugs, mRNA, siRNA, and gene-editing components. This review systematically examines the formulation strategies, biological barriers, and therapeutic applications of lipid nanoparticles (LNPs) and cell-derived nanovesicles for gene delivery. LNPs are typically composed of four essential constituents—ionizable or cationic lipids, helper phospholipids, cholesterol, and PEGylated lipids—each playing a critical role in encapsulation efficiency, cellular uptake, endosomal escape, and in vivo stability. The clinical success of FDA-approved products such as Onpattro (patisiran) and the COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) has unequivocally validated LNP technology as a safe and effective nucleic acid delivery platform. We have discussed the key biological barriers that LNPs must overcome, including nuclease degradation, opsonization and clearance by the mononuclear phagocyte system, cellular internalization, and the rate-limiting step of endosomal escape. Targeting strategies, both passive (enhanced permeability and retention effect) and active (ligand-mediated), are explored for their roles in enhancing therapeutic precision. The review also provides a comparative analysis of synthetic LNPs versus cell-derived nanovesicles (exosomes), highlighting differences in targeting efficiency, biocompatibility, immunogenicity, and stability. Emerging hybrid and bio-inspired systems, including cell membrane-coated nanoparticles and exosome-mimetic vesicles, are discussed as next-generation platforms that synergistically combine the advantages of synthetic and biological carriers. Finally, we have examined the preclinical and clinical progress of LNP-based therapeutics, ongoing translational challenges related to storage stability, immunogenicity, and scalable manufacturing, and future directions incorporating artificial intelligence and selective organ targeting. By integrating fundamental principles of lipid chemistry with advances in nanotechnology and molecular medicine, this review provides a comprehensive framework for the rational design of lipid-based nanoparticles for next-generation gene therapies.