Browning Lipid Nanoparticles Deliver Metabolic Benefits via Transient Conversion of White Adipose Tissue
- 1Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States
Abstract
Therapeutic strategies based on increasing uncoupled respiration (browning) in white adipose tissue (WAT) have great potential for treating obesity-related disorders such as diabetes and steatotic liver disease, but have not had a clinical impact because safe and efficient methods for browning WAT have not been developed. Lipid nanoparticles (LNPs) offer a promising platform for adipose-directed siRNA delivery; however, conventional formulations often exhibit limited activity in adipocytes and can induce inflammatory responses that may restrict repeated administration. Here we demonstrate that LNPs that contain ionizable lipids with three lipid tails and siRNAs targeting TLE3 and ZFP423 can efficiently transfect mature adipocytes and induce browning of WAT in vitro and in vivo while providing the biocompatibility needed for repeated subcutaneous injections. Repeated local administration of BLNPs in diet-induced obese mice resulted in sustained target gene silencing, increased expression of thermogenic markers, altered energy metabolism, and decreased hepatic lipid accumulation despite minimal effects on body weight relative to scramble siRNA controls. Collectively, these findings establish BLNPs as a promising platform for adipose-directed RNA delivery and targeted modulation of thermogenic pathways, providing a strategy for investigating how localized adipose tissue remodeling influences metabolic physiology.
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BibTeX
@misc{sharma2026browning,
title = {{Browning Lipid Nanoparticles Deliver Metabolic Benefits via Transient Conversion of White Adipose Tissue}},
author = {R. Sharma and A. L. Gunawan and Y. He and L. Qi and N. Singhal and J. Lukman and N. Kalindjian and V. Tran and N. Murthy and A. Stahl},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754464},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754464v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Browning Lipid Nanoparticles Deliver Metabolic Benefits via Transient Conversion of White Adipose Tissue
AU - R. Sharma
AU - A. L. Gunawan
AU - Y. He
AU - L. Qi
AU - N. Singhal
AU - J. Lukman
AU - N. Kalindjian
AU - V. Tran
AU - N. Murthy
AU - A. Stahl
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754464
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754464v1
AB - Therapeutic strategies based on increasing uncoupled respiration (browning) in white adipose tissue (WAT) have great potential for treating obesity-related disorders such as diabetes and steatotic liver disease, but have not had a clinical impact because safe and efficient methods for browning WAT have not been developed. Lipid nanoparticles (LNPs) offer a promising platform for adipose-directed siRNA delivery; however, conventional formulations often exhibit limited activity in adipocytes and can induce inflammatory responses that may restrict repeated administration. Here we demonstrate that LNPs that contain ionizable lipids with three lipid tails and siRNAs targeting TLE3 and ZFP423 can efficiently transfect mature adipocytes and induce browning of WAT in vitro and in vivo while providing the biocompatibility needed for repeated subcutaneous injections. Repeated local administration of BLNPs in diet-induced obese mice resulted in sustained target gene silencing, increased expression of thermogenic markers, altered energy metabolism, and decreased hepatic lipid accumulation despite minimal effects on body weight relative to scramble siRNA controls. Collectively, these findings establish BLNPs as a promising platform for adipose-directed RNA delivery and targeted modulation of thermogenic pathways, providing a strategy for investigating how localized adipose tissue remodeling influences metabolic physiology.
ER -