Hybrid Cryomicroneedles Enhance DC Vaccine Efficacy and Function as Non-Typical Artificial Tertiary Lymphoid Structures to Provide Neuroprotective Immunity in Spinal Cord Injury.

Spinal cord injury (SCI) causes permanent neurological deficits, and immune responses play a pivotal role in tissue regeneration and functional recovery. Dendritic cell (DC) vaccines have shown considerable potential for modulating injury-induced immune dysregulation. However, their therapeutic efficacy is limited by factors such as restricted cellular viability, delayed onset of action, and lack of sustained immune activity. Therefore, to address these challenges, a hybrid hydrogel composed of a methacrylate-modified decellularized lymph node extracellular matrix (DLMMA) and porous GelMA (pGelMA) carrying a neuroprotective DC (npDC) vaccine was developed in the form of cryomicroneedles (pG/DL@npDC-cryoMNs), enabling efficient and sustained immunological regulation during SCI treatment. The pG/DL@npDC-cryoMNs enhanced the viability of npDC vaccine and facilitated rapid npDC release, thereby inducing neuroprotective immunity at the injury site during the early stage. In addition, pG/DL@npDC-cryoMNs fostered the formation of a non-typical artificial tertiary lymphoid structure (naTLS) that lacked the complete organized structure of typical TLS yet effectively recruited and engaged immune cells to promote SCI repair. Moreover, pG/DL@npDC-cryoMNs maintained immunomodulatory activity for up to two weeks, facilitating neuronal regeneration in a mouse model of SCI. Overall, these findings highlight the therapeutic potential of pG/DL@npDC-cryoMNs in promoting SCI repair by establishing a neuroprotective immune microenvironment.