Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic...

Area of Science:

• Biotechnology
• Regenerative Medicine
• Molecular Biology

Background:

• Current RNA interference (RNAi) bone anabolic strategies face safety and efficacy challenges due to the absence of osteoblast-specific delivery systems for osteogenic small interfering RNAs (siRNAs).
• Targeted delivery of therapeutic agents to specific cell types is crucial for enhancing treatment efficacy and minimizing off-target effects.

Purpose of the Study:

• To develop and evaluate osteoblast-specific aptamer-functionalized lipid nanoparticles (LNPs) for targeted delivery of osteogenic siRNA.
• To assess the efficacy of this novel RNAi-based strategy in promoting bone formation and improving bone quality in vivo.

Main Methods:

• Screening of aptamer CH6 using cell-SELEX for specific targeting of rat and human osteoblasts.
• Development of CH6 aptamer-functionalized LNPs encapsulating pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA).
• In vitro assessment of osteoblast-selective uptake and in vivo evaluation of gene silencing, bone formation, microarchitecture, mass, and mechanical properties in osteopenic and healthy rodents.

Main Results:

• CH6 facilitated selective uptake of Plekho1 siRNA by osteoblasts in vitro, primarily through macropinocytosis.
• CH6-LNPs-siRNA achieved osteoblast-specific Plekho1 gene silencing in vivo.
• The treatment promoted bone formation, enhanced bone microarchitecture, increased bone mass, and improved mechanical properties in both osteopenic and healthy rodents.

Conclusions:

• Osteoblast-specific aptamer-functionalized LNPs represent a promising new strategy for RNAi-based bone anabolism.
• This approach advances targeted siRNA delivery from the tissue level to the cellular level, improving selectivity and potentially safety.
• The findings support the potential of this technology for treating bone loss conditions and enhancing bone regeneration.