Hyaluronic acid-based supramolecular peptide-drug conjugate prodrug nanosystems for precise multiple myeloma therapy.

Multiple myeloma (MM) is an incurable hematological malignancy with excessive bone marrow infiltration and pro-inflammatory microenvironment. In clinical practice, melphalan, an alkylating agent, and dexamethasone, a glucocorticoid widely used in MM regimens, provide clinical benefits. However, their efficacy is still limited by systemic toxicity, poor tumor selectivity, and the difficulty maintaining a predefined drug ratio at the tumor site. To address these challenges, we designed a supramolecular peptide-drug conjugate prodrug nanosystem (HMD NPs) composed of β-cyclodextrin-modified hyaluronic acid (HA-β-CD) scaffold and dual-drug conjugates, Ada-M-GFLG-D. In this design, MA and DEX are conjugated via a cathepsin B-cleavable GFLG linker and functionalized with adamantane for host-guest assembly, which allows co-delivery of the two drugs at a fixed 1:1 stoichiometric ratio. The resulting HMD NPs exhibited excellent stability, efficient cellular uptake. Ada-M-GFLG-D remains encapsulated within nanoparticles under physiological conditions. However, upon exposure to MM-mimicking intracellular conditions, HMD NPs undergo an enzyme-activation process, rapidly releasing both drugs. Cellular experiments demonstrate potent anti-tumor effects and significant downregulation of inflammatory pathways. In animal models, HMD NPs markedly suppress tumor progression, reducing bone marrow infiltration, relieving osteolytic damage, and showing favorable biocompatibility. These findings provide a promising strategy for improving therapeutic efficacy against MM.