Nanomedicine-Empowered CAR-T Therapy for Multiple Myeloma: Toward Programmable, Durable, and Precision Immunotherapy.

Multiple myeloma (MM) remains a difficult-to-cure hematologic malignancy. Although B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has substantially deepened clinical responses in patients with relapsed/refractory MM, its broader clinical application remains constrained by post-treatment relapse, insufficient response durability, prolonged manufacturing timelines, and limited accessibility. Increasing evidence indicates that relapse after CAR-T therapy in MM arises not from a single mechanism but from the convergence of tumor antigen remodeling, CAR-T cell exhaustion, impaired metabolic fitness, and bone marrow microenvironment-mediated immunosuppression. Nanomedicine provides modular engineering strategies to address these interconnected barriers to therapeutic efficacy. For example, lipid nanoparticles, polymeric carriers, biomimetic nanoplatforms, and targeted delivery systems may optimize ex vivo CAR-T manufacturing, enable in vivo CAR-T cell generation, regulate BCMA antigen density, remodel the bone marrow niche, and facilitate dynamic monitoring of relapse risk. This review systematically examines the major biological mechanisms underlying relapse after CAR-T therapy in MM, with particular emphasis on both the therapeutic potential of nanotechnology and the translational challenges associated with CAR-T manufacturing optimization, in vivo immune programming, bone marrow microenvironment remodeling, and relapse control in the post-BCMA era. By integrating advances in tumor immunology, materials science, and hematologic oncology, this review proposes a conceptual framework and future research priorities for developing faster, more controllable, durable, and accessible CAR-T therapeutic strategies for MM.