Sequential Dual-Targeting Biomimetic Nanovesicles for Bone Marrow–Specific Delivery of Bortezomib in Multiple Myeloma

Yonghua Li^1*Chongyan Lu²Zhifang Xiao¹Hanqing Zhang¹Peng Zhang¹Yang Gao¹Ling Ouyang¹Xianjun He¹Na Han¹Jinfeng Zhang¹Mengshan Guan¹Yueqi Feng¹

• ¹People's Liberation Army General Hospital of Southern Theatre Command, Guangzhou, China
• ²Guangzhou University of Chinese Medicine, Guangzhou, China

We developed engineered cell membrane–biomimetic nanovesicles that integrate the homologous targeting of tumor cell membranes, the homing ability of myeloma cells, and the bone affinity of bisphosphonates to achieve sequential dual targeting of myeloma. These nanovesicles efficiently delivered the first-line drug bortezomib (BTZ) to the bone marrow, increasing its effective concentration and enhancing therapeutic outcomes. BTZ delivered by the nanovesicles modulated apoptosis-related proteins in myeloma cells and promoted cell death, while also reducing neurotoxicity and other adverse effects. This biomimetic strategy showed good biosafety in vivo without inducing inflammatory responses, highlighting its potential as an effective and safe treatment for myeloma. ABSTRACT 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. 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 "bone‐first, tumor‐next" 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. 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 < 0.001), accompanied by reduced systemic toxicity. 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.