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Background: Clinical protocols in osteoporosis treatment could not meet the requirement of increasing local bone mineral density. A local delivery system was brought in to fix this dilemma. The high-energy extracorporeal shock wave (ESW) can travel into the deep tissues with little heat loss. Hence, ESW-driven nanoparticles could be used for local treatment of osteoporosis., Materials and Methods: An extracorporeal shock wave (ESW)--actuated nanomotor (NM) sealed into microneedles (MN) (ESW-NM-MN) was constructed for localized osteoporosis protection. The NM was made of calcium phosphate nanoparticles with a high Young's modulus, which allows it to absorb ESW energy efficiently and convert it into kinetic energy for solid tissue penetration. Zoledronic (ZOL), as an alternative phosphorus source, forms the backbone of the NM (ZOL-NM), leading to bone targeting and ESW-mediated drug release., Results: After the ZOL-NM is sealed into hyaluronic acid (HA)--made microneedles, the soluble MN tips could break through the stratum corneum, injecting the ZOL-NM into the skin. As soon as the ESW was applied, the ZOL-NM would absorb the ESW energy to move from the outer layer of skin into the deep tissue and be fragmented to release ZOL and Ca2+ for anti-osteoclastogenesis and pro-osteogenesis. In vivo, the ZOL-NM increases localized bone parameters and reduces fracture risk, indicating its potential value in osteoporotic healing and other biomedical fields., Conclusion: The ESW-mediated transdermal delivery platform (ESW-NM-MN) could be used as a new strategy to improve local BMD and protect local prone-fracture areas., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)