{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:43:25Z","timestamp":1793317405720,"version":"4.5.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Inefficient bone marrow targeting remains a major barrier to improving clinical outcomes in multiple myeloma (MM). Although bortezomib (BTZ), a first-line proteasome inhibitor, exhibits potent antitumor activity, its short half-life, dose-limiting off-target toxicity, and pronounced neurotoxicity severely constrain therapeutic utility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we report the design of a sequentially dual-targeted biomimetic nanoplatform that integrates the high affinity of alendronate for hydroxyapatite in the bone matrix with the homotypic targeting capability of MM cell membranes, thereby enabling a hierarchical \u201cbone-first, tumor-next\u201d delivery paradigm. This two-stage navigation strategy allows the nanoparticles to anchor specifically within the bone microenvironment and subsequently achieve precise MM cell recognition via membrane adhesion molecules, leading to enhanced intralesional BTZ accumulation and retention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>As a result, proteasome inhibition and apoptosis induction were markedly amplified. Both in vitro and in vivo studies demonstrated that this nanoplatform significantly prolonged survival in MM-bearing mice: all animals in the PBS control group succumbed within 29 days, whereas 100% of BTZ@PLGA\/EM-treated mice survived to day 45 (p &amp;lt; 0.001), accompanied by reduced systemic toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, this work addresses a central challenge of drug delivery within the bone marrow niche and provides a promising strategy with strong translational potential for MM therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbioe.2025.1714613","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T06:27:33Z","timestamp":1763360853000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Sequential dual-targeting biomimetic nanovesicles for bone marrow\u2013specific delivery of bortezomib in multiple myeloma"],"prefix":"10.3389","volume":"13","author":[{"given":"Chongyan","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengshan","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1158\/1078-0432.CCR-10-1950","article-title":"Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events","volume":"17","author":"Arastu-Kapur","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2301748","DOI":"10.1002\/smll.202301748","article-title":"Encapsulation of nano\u2010bortezomib in apoptotic stem cell\u2010derived vesicles for the treatment of multiple myeloma","volume":"19","author":"Cao","year":"2023","journal-title":"Small"},{"key":"B4","doi-asserted-by":"publisher","first-page":"4526","DOI":"10.1021\/acs.nanolett.7b02129","article-title":"Receptor and microenvironment dual-recognizable nanogel for targeted chemotherapy of highly metastatic malignancy","volume":"17","author":"Chen","year":"2017","journal-title":"Nano Lett."},{"key":"B44","doi-asserted-by":"publisher","first-page":"6859","DOI":"10.1182\/bloodadvances.2023010139","article-title":"HAPLN1 matrikine: a bone marrow homing factor linked to poor outcomes in patients with MM","volume":"7","author":"Chang","year":"2023","journal-title":"Blood Adv."},{"key":"B5","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1111\/ejh.12870","article-title":"Nanoparticle delivery systems, general approaches, and their implementation in multiple myeloma","volume":"98","author":"De la Puente","year":"2017","journal-title":"Eur. J. Haematol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.jconrel.2018.08.034","article-title":"Nanomedicines for the treatment of hematological malignancies","volume":"287","author":"Deshantri","year":"2018","journal-title":"J. Control. Release"},{"key":"B7","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/s41565-022-01310-1","article-title":"Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma","volume":"18","author":"Detappe","year":"2023","journal-title":"Nat. Nanotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"Donk","year":"2021","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1016\/j.cell.2016.05.080","article-title":"A BH3 mimetic for killing cancer cells","volume":"165","author":"Green","year":"2016","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1904742","DOI":"10.1002\/adma.201904742","article-title":"CD44\u2010Specific A6 short peptide boosts targetability and anticancer efficacy of polymersomal epirubicin to orthotopic human multiple myeloma","volume":"31","author":"Gu","year":"2019","journal-title":"Adv. Mater."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e2215711120","DOI":"10.1073\/pnas.2215711120","article-title":"In vivo bone marrow microenvironment siRNA delivery using lipid\u2013polymer nanoparticles for multiple myeloma therapy","volume":"120","author":"Guimar\u00e3es","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"8080","DOI":"10.1021\/jacs.0c01823","article-title":"Intracellular photoactivation of caspase-3 by molecular glues for spatiotemporal apoptosis induction","volume":"142","author":"Hentzen","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"B13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nrc2189","article-title":"Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets","volume":"7","author":"Hideshima","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"B14","doi-asserted-by":"crossref","first-page":"1807941","DOI":"10.1002\/adfm.201807941","article-title":"Bortezomib dendrimer prodrug\u2010based nanoparticle system","volume":"29","author":"Hu","year":"2019","journal-title":"Adv. Funct. Mater."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7509","DOI":"10.1038\/s41467-023-43416-7","article-title":"Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma","volume":"14","author":"Larson","year":"2023","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.1021\/acsabm.0c01455","article-title":"Calcium-bisphosphonate nanoparticle platform as a prolonged nanodrug and bone-targeted delivery system for bone diseases and cancers","volume":"4","author":"Lin","year":"2021","journal-title":"ACS Appl. Bio Mater."},{"key":"B17","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrclinonc.2016.206","article-title":"Proteasome inhibitors in cancer therapy","volume":"14","author":"Manasanch","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1601119","DOI":"10.1002\/adhm.201601119","article-title":"Bisphosphonate\u2010functionalized imaging agents, anti\u2010tumor agents and nanocarriers for treatment of bone cancer","volume":"6","author":"Nadar","year":"2017","journal-title":"Adv. Healthc. Mater."},{"key":"B19","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1532\/IJH97.07030","article-title":"Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma","volume":"86","author":"Ozaki","year":"2007","journal-title":"Int. J. Hematol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2107883","DOI":"10.1002\/adma.202107883","article-title":"Cancer\u2010cell\u2010biomimetic nanoparticles for targeted therapy of multiple myeloma based on bone marrow homing","volume":"34","author":"Qu","year":"2022","journal-title":"Adv. Mater."},{"key":"B21","first-page":"299","article-title":"Cancer cell cycles","volume":"86","author":"Sherr","year":"1996","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"10287","DOI":"10.1073\/pnas.1401337111","article-title":"Engineered nanomedicine for myeloma and bone microenvironment targeting","volume":"111","author":"Swami","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s11899-018-0456-8","article-title":"Updates in the pathology of precursor lymphoid neoplasms in the revised fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues","volume":"13","author":"Wenzinger","year":"2018","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/35040607","article-title":"Structural basis for the activation of 20S proteasomes by 11S regulators","volume":"408","author":"Whitby","year":"2000","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2007787","DOI":"10.1002\/adma.202007787","article-title":"Daratumumab immunopolymersome\u2010enabled safe and CD38\u2010targeted chemotherapy and depletion of multiple myeloma","volume":"33","author":"Yu","year":"2021","journal-title":"Adv. Mater."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.3390\/ijms20061451","article-title":"Mechanisms of chemotherapy-induced peripheral neuropathy","volume":"20","author":"Zaj\u0105czkowska","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1038\/s41565-024-01736-9","article-title":"A bispecific nanosystem activates endogenous natural killer cells in the bone marrow for haematologic malignancies therapy","volume":"19","author":"Zhang","year":"2024","journal-title":"Nat. Nanotechnol."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1714613\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T06:27:35Z","timestamp":1763360855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1714613\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":27,"alternative-id":["10.3389\/fbioe.2025.1714613"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2025.1714613","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"article-number":"1714613"}}