Lysosome-triggered nanotherapy packages osteoclast apoptotic bodies with pro-anabolic lipids to couple anti-resorption and bone formation.

Osteoporosis remains challenging to treat because no approved therapy can simultaneously suppress bone resorption and stimulate bone formation. Here we report a lysosome-triggered nanotherapy that converts osteoclast death into a regenerative signal. We first synthesized docosahexaenoyl ceramide (DHA-ceramide) by replacing the native fatty acid of ceramide with docosahexaenoic acid and encapsulated it in aspartate-modified liposomes (Asp-Lip@Cer) to target osteoclasts. After cellular uptake, lysosomal acid ceramidase cleaves DHA-ceramide to release sphingosine (SPH) and DHA. Asp-Lip@Cer selectively disrupts the osteoclast lysosomal membrane and triggers apoptosis, and produces abundant osteoclast-derived apoptotic bodies (OC-ABs) enriched with SPH and DHA that are efficiently internalized by mesenchymal stem cells and endothelial progenitor cells. In recipient cells, DHA activates AKT signaling to promote osteogenesis, whereas SPH is converted to S1P to activate ERK signaling and enhance angiogenesis. In an ovariectomized mouse model of postmenopausal osteoporosis, systemic administration of Asp-Lip@Cer suppressed osteoclast activity, improved bone mineral density and trabecular architecture, increased osteopontin expression, and expanded CD31⁺/EMCN⁺ vasculature. This "one-stone-two-birds" strategy unites potent anti-resorptive activity with amplified pro-anabolic effects in a single platform, offering a promising therapeutic paradigm for osteoporosis and other disorders of impaired bone remodeling. ONE SENTENCE SUMMARY: Lysosome-triggered Asp-Lip@Cer nanotherapy turns osteoclast death into SPH/DHA-rich apoptotic bodies, simultaneously suppressing bone resorption and promoting bone formation.