Precisely targeting of engineered nanovesicles to implanted scaffolds via click chemistry for microenvironment regulation in acute spinal cord injury

Spinal cord injury (SCI) requires sufficient and sustained therapeutic intervention for microenvironment regulation in the acute phase. However, systemic drug administration is often ineffective due to non-specific distribution within the damaged spinal cord. While local implantation systems have gained attention for site-specific delivery, they are often constrained by spatial limitations and present challenges in designing sequential release profiles. Herein, we reported the development of a composite drug delivery system integrating intranasal administration with local implantation. Specifically, the locally implanted scaffold was modified with dibenzocyclooctyne (DBCO) groups (dGN). Azide group-functionalized nanovesicles (aNVs), extruded from engineered mesenchymal stem cells, were continuously administered intranasally. aNVs accumulated within the lesion by undergoing a bio-orthogonal click chemistry reaction with dGN, which markedly enhanced their local distribution and retention. The composite drug delivery system, dGN&aNVs, effectively promoted acute microenvironmental regulation, hindlimb motor function recovery, associated symptoms alleviation, and tissue repair and regeneration following SCI in rats. This work presents a robust and minimally invasive platform designed for the precision-targeted therapy of central nervous system diseases.