Programmable Lipid Nanoparticles for Precision Drug Delivery: A Four-Domain Model Perspective

Abstract

Programmable lipid nanoparticles (LNPs) offer precise spatiotemporal control over drug distribution and release, a critical advancement for treating complex diseases like cancer and genetic disorders. While existing reviews offer extensive insights into LNP development, this work introduces a novel model that dissects key components of LNP design, providing a framework to enhance the rational design of programmable LNPs. This review introduces a novel Four-Domain Model - Architecture, Interface, Payload, and Dispersal - providing a modular perspective that emphasizes the programmability of LNPs. We explore the dynamics between LNPs components and their environment throughout their lifecycle, focusing on thermodynamic stability during synthesis, storage, delivery, and drug release. Through these four distinct but interconnected domains, we introduce the concept of input stimuli, functional components, and output responses. This modular approach offers new perspectives for the rational design of programmable nanocarriers for exquisite control over payload release while minimizing off-target effects. Advances in bioinspired design principles could lead to LNPs that mimic natural biological systems, enhancing their biocompatibility and functionality. This review summarizes recent advancements, identifies challenges, and offers outlooks for programmable LNPs, emphasizing their potential to evolve into more intelligent, naturally integrated systems that enhance scalability and reduce side effects.