Bone Marrow-TargetedLiposomes Loaded with BortezomibOvercome Multiple Myeloma Resistance

Multiple myeloma (MM) poses a significant therapeutic challenge due to its persistent progression and low survival rate. Although the proteasome inhibitor bortezomib has revolutionized MM treatment, MM aggressiveness and drug resistance remain critical concerns. To tackle this problem, we developed AMD3100-targeted Bortezomib Liposomes (ATBL) designed for the targeted delivery of bortezomib to MM cells. Uptake of ATBL into MM cells was dependent on CXCR4 and was enhanced compared to nontargeted liposomes, both <i>in vitro</i> and <i>in vivo</i>. Treating MM-bearing mice with ATBL achieved superior therapeutic efficacy compared to treatment with free bortezomib or nontargeted bortezomib-loaded liposomes. Notably, the therapeutic activity of ATBL was limited in mice inoculated with CXCR4-knockdown MM cells, highlighting CXCR4 as a potential biomarker for ATBL response. Importantly, ATBL was effective against an aggressive and bortezomib-resistant MM clone both <i>in vitro</i> and <i>in vivo</i>. Toxicity and biodistribution profiles demonstrated the safety and bone marrow-targeting ability of ATBL. Collectively, this study highlights ATBL as a promising next-generation proteasome inhibitor-based therapy that incorporates bone marrow-targeting ability and sensitizing elements to overcome drug resistance in MM.