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The challenges in managing MM include selecting chemotherapy regimens that effectively modulate the myeloma microenvironment and delivering them to the bone marrow with high efficacy and minimal toxicity. Herein, a novel bone marrow targeting strategy using c(RGDfk) peptide\u2010modified liposomes loaded with chemotherapeutics is developed, which can specifically recognize and hitchhike neutrophils following systemic administration, capitalizing on their natural aging process to facilitate precise drug delivery to the bone marrow, thus minimizing off\u2010target effects. On the one hand, c(RGDfk)\u2010functionalized liposomes containing carfilzomib (CRLPs) successfully transformed macrophages from M2 phenotype to M1 phenotype, enhancing immunotherapeutic responses. On the other hand, c(RGDfk)\u2010functionalized liposomes encapsulating BMS\u2010202 (BRLPs), a small molecule checkpoint inhibitor, interrupted the PD\u20101\/PD\u2010L1 axis and promoted the infiltration of cytotoxic T cells. The co\u2010administration of CRLPs and BRLPs successfully delivered drugs to bone marrow, leading to significant modulation of the myeloma microenvironment, reduced tumor growth, and improved survival time of MM\u2010bearing mouse models. These findings introduced an alternative approach to modulating the myeloma microenvironment and underscored the efficacy of hitchhiking neutrophils for bone marrow drug delivery. This strategy show advantages over traditional drug delivery methods in terms of improved efficacy and lowered toxicity.<\/jats:p>","DOI":"10.1002\/advs.202409895","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T08:50:27Z","timestamp":1734339027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeted Delivery of c(RGDfk)\u2010Modified Liposomes to Bone Marrow Through In Vivo Hitchhiking Neutrophils for Multiple Myeloma Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Huiwen","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Hematology Union Hospital Tongji Medical College Huazhong University of Science &amp; Technology  Wuhan Hubei 430022 China"},{"name":"Key lab of Molecular Biological Targeted Therapies of the Ministry of Education Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 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