PharmaceuticsMay 4, 2026

Making Bone-Targeted Lipid Nanoparticles Modified with Alendronate for Delivering mRNA

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated May 5, 2026

Abstract

Post-conjugation modification of lipid nanoparticles results in significantly superior bone affinity compared to pre-conjugation.

Bone-targeting lipid nanoparticles (LNPs) were developed using two different alendronate modification strategies.
Hydroxyapatite binding assays indicated that LNPs from the post-conjugation method had stronger binding to bone than those from the pre-conjugation method.
Ex vivo experiments demonstrated that post-conjugation LNPs exhibited enhanced bone-binding capability over unmodified LNPs.
Optimized alendronate-functionalized LNPs showed efficient cellular uptake and functional mRNA translation in bone marrow stem cells with minimal cytotoxicity.
Studies in mice revealed preferential accumulation of alendronate-LNPs in bone tissues, with successful translation of GFP mRNA in these areas.
Histopathological analysis confirmed the biosafety of the formulated lipid nanoparticles.

Simplified

Bone-targeted drug delivery systems hold great promise for treating skeletal diseases, yet the optimal strategy for functionalizing lipid nanoparticles (LNPs) with bone-homing ligands remains insufficiently explored. Herein, we compared two alendronate sodium (Alen) modification approaches (pre-conjugation and post-conjugation) for constructing bone-targeted LNPs capable of delivering mRNA to skeletal tissues.LNPs were fabricated via microfluidic mixing, and the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-alendronate conjugate (DSPE-PEG-Alen) required for the pre-conjugation method was synthesized. The bone-targeting ability of LNPs prepared by the two Alen modification strategies was evaluated using anhydroxyapatite (HAP) binding assay. Furthermore, the physicochemical properties, bone-targeting performance, mRNA delivery efficiency, and biosafety of the LNPs prepared by the post-conjugation method were assessed through cellular uptake,imaging, and other methods.Hydroxyapatite binding assays revealed that the post-conjugation strategy afforded significantly superior bone affinity compared to the pre-conjugation approach. In addition, ex vivo bone fragment binding experiments further confirmed that the bone-targeting LNPs prepared by the post-conjugation method exhibited stronger bone-binding capability compared to unmodified LNPs. The optimized Alen-LNPs demonstrated efficient cellular uptake and functional mRNA translation in bone marrow mesenchymal stem cells with negligible cytotoxicity.studies in mice confirmed the preferential accumulation of Alen-LNPs in bone tissues, with successful green fluorescent protein (GFP) mRNA translation detected in bone tissue sections. Histopathological analysis confirmed the biosafety of the formulation.This study establishes the post-conjugation strategy as the superior approach for Alen functionalization of LNPs, providing a robust and reproducible platform for bone-targeted mRNA therapeutics. Background/Objectives: Methods: Results: Conclusions: in vitro in vivo In vivo

Funding

Competing interests

The authors declare no competing interests.

PubMed

Making Bone-Targeted Lipid Nanoparticles Modified with Alendronate for Delivering mRNA

Abstract

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Competing interests

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Abstract

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