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Hence, targeting the acidic microenvironment and RANKL production may break this vicious cycle to rescue osteoporosis. To achieve this, an acid\u2010responsive and neutralizing system with high in vivo gene editing capacity is developed by loading sodium bicarbonate (NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    ) and RANKL\u2010CRISPR\/Cas9\u00a0(RC) plasmid in a metal\u2013organic framework. This results showed ZIF8\u2010NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    @Cas9 (ZNC) effective neutralized acidic microenvironment and inhibited ROS production . Surprisingly, nanoparticles loaded with NaHCO\n                    <jats:sub>3<\/jats:sub>\n                    and plasmids show higher transfection efficiency in the acidic environments as compared to the ones loaded with plasmid only. Finally, micro\u2010CT proves complete reversal of bone volume in ovariectomized mice after ZNC injection into the bone remodeling site. Overall, the newly developed nanoparticles show strong effect in neutralizing the acidic microenvironment to achieve bone protection through promoting osteogenesis and inhibiting osteolysis in a bidirectional manner. This study provides new insights into the treatment of osteoporosis for biomedical and clinical therapies.\n                  <\/jats:p>","DOI":"10.1002\/smll.202307595","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T07:29:24Z","timestamp":1703143764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Breaking Osteoclast\u2010Acid Vicious Cycle to Rescue Osteoporosis via an Acid Responsive Organic Framework\u2010Based Neutralizing and Gene Editing Platform"],"prefix":"10.1002","volume":"20","author":[{"given":"Wenzheng","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine Medical College Yangzhou University Yangzhou 225001 P. R. China"},{"name":"Department of Orthopedics Affiliated Hospital of Yangzhou University Yangzhou 225009 P. R. 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