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Previously, we showed that while tartrate\u2010resistant acid phosphatase (TRAP) binding peptide (TBP)\u2010targeted polymeric nanoparticles (TBP\u2010NP) delivering a bone regenerative Wnt agonist improved NP fracture accumulation and expedited healing compared with controls, there was also significant MPS accumulation. Here we show that TBP\u2010NPs are taken up by liver, spleen, lung, and bone marrow macrophages (M\u03d5), with 76\u2009\u00b1\u20094%, 49\u2009\u00b1\u200911%, 27\u2009\u00b1\u20099%, and 92\u2009\u00b1\u20095% of tissue\u2010specific M\u03d5 positive for NP, respectively. Clodronate liposomes (CLO) significantly depleted liver and spleen M\u03d5, resulting in 1.8\u2010fold and 3\u2010fold lower liver and spleen and 1.3\u2010fold and 1.6\u2010fold greater fracture and na\u00efve femur accumulation of TBP\u2010NP. Interestingly, depletion and saturation of MPS using 10\u2010fold greater TBP\u2010NP doses also resulted in significantly higher TBP\u2010NP accumulation at lungs and kidneys, potentially through compensatory clearance mechanisms. The higher NP dose resulted in greater TBP\u2010NP accumulation at na\u00efve bone tissue; however, other MPS tissues (i.e., heart and lungs) exhibited greater TBP\u2010NP accumulation, suggesting uptake by other cell types. Most importantly, neither M\u03d5 depletion nor saturation strategies improved fracture site selectivity of TBP\u2010NPs, possibly due to a reduction of M\u03d5\u2010derived osteoclasts, which deposit the TRAP epitope. Altogether, these data support that MPS\u2010mediated clearance is a key obstacle in robust and selective fracture accumulation for systemically administered bone\u2010targeted DDS and motivates the development of more sophisticated approaches to further improve fracture selectivity of DDS.<\/jats:p>","DOI":"10.1002\/jbm.a.37279","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T15:01:25Z","timestamp":1627484485000},"page":"229-238","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Macrophage depletion increases target specificity of bone\u2010targeted nanoparticles"],"prefix":"10.1002","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3081-5115","authenticated-orcid":false,"given":"Marian A.","family":"Ackun\u2010Farmmer","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering University of Rochester  Rochester New York 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