Unlocking the full therapeutic potential of lipid nanoparticles through extrahepatic delivery

The earliest iteration of LNPs was the development of liposomes in the 1960s, with the first liposome-based drug product, Doxil, receiving FDA approval in 1995. In the early 1990s, a second generation of LNPs emerged, including solid lipid nanoparticles and nanostructured lipid carriers. A widely accepted distinction between these systems is that solid lipid nanoparticles possess a solid lipid core, whereas liposomes are characterized by their aqueous core. Decades of dedicated research have culminated in groundbreaking advancements in LNP-based therapeutics. These efforts led to the development of small interfering RNA-loaded LNPs (LNP/siRNA) treatments for liver diseases in 2018 and the revolutionary messenger RNA-loaded LNPs (LNP/mRNA)-based COVID-19 vaccines in record time during the pandemic. Notably, it took less than a year to design, test, and deliver these mRNA vaccines – an unprecedented scientific milestone. These remarkable achievements mark a transformative era in drug delivery, underscoring the immense potential of LNP platforms. Because of their versatility, LNPs have become the most popular delivery systems in both academic research and industrial applications. Beyond liver-targeted and infectious disease treatments, LNPs hold significant promises for addressing a broad spectrum of medical challenges.

Despite the great success, a major limitation of LNP-based delivery systems is their inherent liver tropism following systemic administration. This liver-centric accumulation, often referred to as a bottleneck, hinders the broader application of LNPs and limits their therapeutic potential. Recent breakthroughs in in vivo gene engineering, facilitated by LNP platforms, have intensified the need for strategies enabling efficient extrahepatic delivery.

A team of drug delivery scientists led by Fanfei Meng from the University of Massachusetts Lowell, recently explored the key factors contributing to the liver accumulation of LNPs and discussed strategies to overcome this challenge. The team published their review in Nano Research on April 22, 2025.

“In this review, we explored the key factors contributing to the liver accumulation of LNPs and discuss strategies to overcome this challenge, as shown in Table 1. Specifically, we highlight approaches to modulate LNP composition — including ionizable lipids, helper lipids, cholesterol, and other critical components — to facilitate extrahepatic accumulation. We further discuss recent advancements in surface modification techniques designed to redirect LNPs to organs beyond the liver. Additionally, we highlight recent progress in local delivery approaches, which offer a direct and effective alternative for achieving extrahepatic delivery. While significant progress has been made, challenges remain in achieving consistent and efficient extrahepatic delivery. To address this, we propose future research directions to guide future research in fully unleashing the therapeutic potential of LNP-based delivery systems.

This work was supported by a start-up package from the University of Massachusetts Lowell to Fanfei Meng.

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.