Diverse structures and shapes of lipid-based nanoparticles: Toward clinical translation

Lipid-based nanoparticles (LbNPs) have emerged as versatile and clinically relevant drug delivery platforms, attracting growing interest from both academia and the pharmaceutical industry. Their tunable size, intrinsic biocompatibility, and structural adaptability enable the delivery of a broad spectrum of therapeutic cargos, including small molecules, nucleic acids, and biologics. Recent clinical breakthroughs, most notably RNA-based therapeutics such as Onpattro® and the mRNA vaccine Comirnaty®, have established ionizable lipid nanoparticles (iLNPs) as a transformative technology in modern medicine, underscoring the translational potential of LbNPs. Beyond clinically established iLNPs, advances in lipid self-assembly have enabled the generation of nanoparticles with diverse internal structures, morphologies, and shapes, offering new opportunities to modulate biological interactions, biodistribution, and intracellular trafficking. A wide range of lipid building blocks supports the rational design of tailored nanoformulations for distinct applications. This review provides a comprehensive overview of recent progress in lipid-based nanoparticle research, with a particular focus on structural and compositional diversity and its implications for biological performance. We critically discuss current preparation and characterization methods, therapeutic applications, and the evolving clinical trial landscape. Finally, we address key challenges in manufacturability, reproducibility, and regulatory considerations, emphasizing the need to balance structural innovation with scalability and clinical feasibility of LbNPs. • Lipid-based nanoparticles (LbNPs) show diverse shapes beyond spherical particles. • LbNPs structure governs biodistribution, cellular uptake, and efficacy in vivo. • LbNPs' structural complexity limits manufacturing, scalability, and translation. • Diverse lipid nanoparticles enable new therapies for unmet needs.