Customized extracellular vesicles targeting lysosomal biogenesis deliver therapeutic cargo for intervertebral disc degeneration treatment.

Extracellular vesicles (EVs) have gained prominence as advanced drug delivery systems due to their inherent merits. Recent advancements highlight their utility in transporting therapeutic proteins with significant progress in targeted therapies. To optimize EV efficacy, engineering strategies focus on enhancing cargo encapsulation efficiency. The robust interaction between immunoglobulin G Fc fragments and the cytoplasmic receptor TRIM21 offers a novel framework for stable cargo loading. This study identifies Ras-related GTP-binding protein D (RRAGD) as a critical regulator of lysosomal biogenesis and function. Leveraging Fc-TRIM21 interactions, engineered EVs encapsulating RRAGD were developed. Surface modification with CAP peptides enhanced nucleus pulposus (NP) cell-targeting specificity of EVs. In vitro and in vivo experiments demonstrated that engineered EVs ameliorated lysosomal dysfunction and suppressed apoptosis in NP cells, and slowed intervertebral disc degeneration (IDD) progression. The mechanistic analysis revealed the functional co-localization of RRAGD with lysosomal marker LAMP1 and lysosomal regeneration transcription factor TFEB, indicating lysosomal targeting. This study establishes CAP-modified engineered EVs based on the Fc/TRIM21 platform as a therapeutic strategy to restore lysosomal homeostasis and counteract IDD pathogenesis, underscoring the potential of EV-based therapies for degenerative disc diseases.