A DNA aptamer targeting RANKL and its nanoparticle-mediated delivery ameliorate osteoporotic bone loss.

Osteoporosis management remains challenging, partly due to the poor bioavailability of drugs in bone and the systemic side effects of current treatments. To address this, we engineered a targeted nanomedicine therapy using a DNA aptamer that specifically binds RANKL, a pivotal regulator of bone resorption. The aptamer is conjugated to PEGylated mesoporous silica nanoparticles (MSNs) to create a novel agent, aptRANKL@MSN. The nanoparticle platform enhances the aptamer's stability and may promote its accumulation in bone tissue, likely through a combination of passive targeting and the intrinsic affinity of the aptamer's phosphate backbone for bone mineral. In an ovariectomized mouse model of osteoporosis, aptRANKL@MSN treatment effectively reversed bone loss, restoring bone mass, microarchitecture, and mechanical strength to levels comparable to healthy controls. The therapy demonstrated a dual action, suppressing bone resorption while also enhancing bone formation as evidenced by increased mineral apposition rate and serum P1NP levels, thereby rebalancing bone homeostasis. Crucially, this bone-accumulating approach achieved superior efficacy over free aptamer and the conventional drug alendronate, while showing no significant toxicity over the 4-week treatment period. Our findings present aptRANKL@MSN as a precise and potent therapeutic strategy with strong potential for clinical translation in osteoporosis.