Bioactive materialsAug 29, 2026

Using mRNA nanoparticles to fix cholesterol balance and help heal age-related bone damage

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 30, 2026

Abstract

LNP@A improved bone regeneration in an aged rat defect model.

ABCA1 palmitoylation is linked to its localization in lysosomes and the transport of cholesterol associated with autophagy inhibition and cellular aging.
Perturbing ABCA1 palmitoylation leads to increased cholesterol accumulation within cells and reduced osteogenesis.
A lysosome-targeted depalmitoylase was engineered to selectively target and modulate ABCA1 localization.
Targeted delivery of RA mRNA using low-inflammatory liposomes successfully reduced cholesterol levels in lysosomes and mitigated senescence in aged bone marrow stem cells.
The treatment restored autophagy and enhanced the osteogenic potential of aged bone marrow stem cells.

Simplified

Cholesterol regulates autophagy and aging, yet its role in bone marrow mesenchymal stem cell (BMSC) senescence remains unclear. We demonstrate that ABCA1 palmitoylation is associated with its lysosomal localization and lysosome-associated cholesterol transport, thereby contributing to autophagy inhibition, senescence, and impaired osteogenesis. However, directly perturbing ABCA1 palmitoylation impaired cholesterol efflux through plasma membrane-localized ABCA1, increased cellular cholesterol accumulation, and inhibited osteogenesis. To selectively depalmitoylate lysosomal ABCA1, we engineered a lysosome-targeted depalmitoylase, RAB7-APT2 (RA), by fusing RAB7 to APT2, the primary depalmitoylase of ABCA1. Aging-cell-targeted low-inflammatory liposomes were synthesized to deliver RA mRNA, yielding dual-targeted lipid nanoparticle (LNP@A). LNP@A selectively modulated lysosomal ABCA1 localization, reduced lysosomal cholesterol accumulation, restored autophagy, and alleviated senescence in aged BMSCs. Consequently, LNP@A enhanced osteogenesis in vitro and improved bone regeneration in an aged rat defect model. These findings reveal a role for ABCA1 spatial regulation in BMSC aging and provide a targeted strategy for age-related bone regeneration.

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Using mRNA nanoparticles to fix cholesterol balance and help heal age-related bone damage

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