Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery

Nat Nanotechnol. 2025 Jan;20(1):132-143. doi: 10.1038/s41565-024-01747-6.

Lulu Xue ^# ¹, Gan Zhao ^# ², Ningqiang Gong ^# ¹, Xuexiang Han ¹, Sarah J Shepherd ¹, Xinhong Xiong ³, Zebin Xiao ², Rohan Palanki ¹, Junchao Xu ¹, Kelsey L Swingle ¹, Claude C Warzecha ⁴, Rakan El-Mayta ¹, Vivek Chowdhary ⁴, Il-Chul Yoon ¹, Jingcheng Xu ¹, Jiaxi Cui ³ ⁵, Yi Shi ⁶, Mohamad-Gabriel Alameh ⁷ ⁸, Karin Wang ⁹, Lili Wang ⁴, Darrin J Pochan ⁶, Drew Weissman ⁷ ⁸, Andrew E Vaughan ², James M Wilson ⁴, Michael J Mitchell ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3 Yangtze Delta Region Institute (Huzhou), University of Electronic Science and Technology of China, Huzhou, China.
4 Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5 Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China.
6 Department of Materials Science and Engineering, University of Delaware, Newark, Delaware, USA.
7 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
8 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
9 Department of Bioengineering, Temple University, Philadelphia, Pennsylvania, USA.
10 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
11 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
12 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
13 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
14 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
15 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. mjmitch@seas.upenn.edu.
# Contributed equally.

PMID: 39354147 DOI: 10.1038/s41565-024-01747-6

Abstract

Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si₅-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-165603

Si5-N14

Liposome

Liposome; VEGFR; FGFR

Inflammation/Immunology; Cardiovascular Disease; Cancer

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