Jordan Kambanis, Lauren A. Lowe, Jingyi Yao, Zhenxu Yang, Shaoxue Zeng, Ken‐Tye Yong, Ling Zhu, Yi Shen
Lipid nanoparticles (LNPs) have emerged as a powerful platform for nucleic acid delivery, exemplified by their success in COVID‐19 mRNA vaccines. Despite this, persistent challenges in formulation, manufacturing, stability, and intracellular delivery efficiency remain. In this review, we provide an overview of conventional LNP formulations and microfluidic methods of production. We also discuss recent advances in organ‐ and cell‐specific targeting and strategies to enhance endosomal escape, which are central to improving the precision and efficacy of LNP‐mediated delivery. Particular emphasis is placed on emerging approaches that enhance targeting and uptake, including hybrid extracellular vesicle‐LNP systems. Finally, we further discuss innovations in formulation and manufacturing, such as the integration of artificial intelligence to optimize LNP design and achieve reproducible, scalable production. Logistical and economic barriers to widespread LNP use are also examined, with a focus on strategies to improve thermostability, which is critical for reducing distribution costs and expanding global access. Collectively, these developments underpin both the current limitations and future potential of LNP therapeutics. Continued advances in targeting, endosomal escape, stability, and computational optimization will be pivotal in establishing LNPs as the gold standard for nanomedicine‐based drug delivery.