Bone Marrow Homing and GPRC5D‐Targeting Engineered Cell Membrane‐Camouflaged Hypoxia‐Responsive Nanoparticles for Multiple Myeloma Therapy

ABSTRACT

Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by malignant proliferation of plasma cells in the bone marrow. The bone marrow barrier limits the drug accumulation following conventional systemic administration, leading to incomplete tumor eradication. Thus, there is an urgent need to develop drug delivery systems capable of enhancing bone marrow accumulation and enabling precise recognition and efficient elimination of myeloma cells. Herein, genetically engineered myeloma cell membranes expressing anti‐GPRC5D single‐chain variable fragment (scFv) (aG‐MM) are employed to cloak bortezomib (BTZ)‐loaded hypoxia‐responsive nanoparticles (BTZ‐hr‐NPs). The resulting aG‐MM@BTZ‐hr‐NPs enable stepwise targeting: first, by mimicking the intrinsic bone marrow homing behavior of MM cells to facilitate nanoparticles accumulation within the bone marrow; and subsequently, through anti‐GPRC5D scFv‐mediated specific recognition of GPRCD5‐positive MM cells to enhance cellular uptake. Upon exposure to the hypoxic MM microenvironment, the nanoparticles undergo rapidly disintegration, triggering accelerated BTZ release. The released BTZ effectively inhibits proteasome activity, promoting apoptosis and modulating NF‐κB signaling, ultimately leading to MM cell death. In an orthotopic MM mouse model, aG‐MM@BTZ‐hr‐NPs effectively suppresses tumor progression. This genetically engineered, stimuli‐responsive nanoplatform providing a promising strategy of efficient targeted drug delivery and MM therapy.