NFATc1-targeted siRNA microdroplets prevent radiation-induced osteoporosis by coordinating bone-immune crosstalk.

Unlabelled: Radiation-induced bone loss, driven by osteoclast activation, involves the transcription factor nuclear factor of activated T-cells cytoplasmic 1 (NFATc1)-mediated signaling. This study developed NFATc1 siRNA-loaded microdroplets (NFATc1/MDs) to mitigate skeletal damage post-radiotherapy.

Methods: NFATc1/MDs were synthesized and characterized using TEM and confocal microscopy. Biocompatibility was tested in hBMSCs and RAW 264.7 macrophages. Osteoclastogenesis, osteogenesis, and adipogenesis were assessed in vitro, and therapeutic efficacy was evaluated in a rat radiation-induced bone loss model.

Results: NFATc1/MDs exhibited a core-shell structure, high biocompatibility, and efficient cellular uptake. They suppressed osteoclastogenesis without impairing osteogenic/adipogenic differentiation and modulated macrophage activity post-irradiation. In vivo, NFATc1/MDs preserved bone microstructure, reduced osteoclast numbers, and downregulated NFATc1, cathepsin K (CTSK), and tumor necrosis factor-alpha (TNF-α) expression.

Conclusions: NFATc1/MDs effectively inhibited osteoclast-mediated bone resorption and inflammation, offering a targeted strategy to prevent radiation-induced bone loss. This biocompatible platform demonstrates potential for clinical translation in radiotherapy-associated skeletal complications.