Nucleic Acid Nanomaterials Targeting Autophagy in Bone Regeneration

Impairment or irreversible loss of bone tissue function remains a prevalent clinical challenge, frequently compounded by donor scarcity, perioperative infection, and immune-mediated rejection, which collectively constrain therapeutic success rates. Novel functional nanomaterials based on nucleic acids-endowed with superior biocompatibility, predictable biodegradability, negligible systemic toxicity, and an abundance of programmable modification sites-have emerged as versatile platforms in bone tissue engineering. Currently, these materials are principally exploited across four interrelated domains: sustained release, bone targeting, scaffold materials for bone regeneration, and bioimaging, all aimed at orchestrating efficient bone regeneration. Recent mechanistic investigations into nano-bio interactions reveal that autophagy, a conserved catabolic pathway in eukaryotes that maintains energetic and metabolic homeostasis, critically governs skeletal repair by directing the timely degradation of intracellular cargo and the turnover of damaged organelles. Through direct modulation of osteoclast and osteoblast differentiation, autophagy fine-tunes the coupled process of bone remodeling. Concurrently, it shapes the regenerative milieu by reprogramming immune cell responses. Consequently, targeted modulation of autophagy represents a rational and promising strategy through which nucleic acid nanomaterials can accelerate bone regeneration. This review synthesizes current knowledge on the contributions of nucleic acid nanomaterials to bone healing, delineates the regulatory functions of autophagy in skeletal regeneration, and explains how these nanomaterials exploit autophagy as a mechanistic lever to enhance bone repair.