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Inflammatory responses play a crucial role in the pathophysiology of spinal cord injury (SCI) and developing new approaches to establish an anti-inflammatory environment for the promotion of neuroregeneration holds promise as a potential approach. In this study, our aim was to investigate the potential of combining an acellular spinal cord scaffold (ASCS) with quercetin-loaded bovine serum albumin (Qu/BSA) nanoparticles (NPs) for the treatment of SCI. The ASCS was prepared using physical and chemical methods, while the Qu/BSA NPs were prepared through a desolvation technique. The NPs exhibited favorable characteristics, including a mean size of 203 nm, a zeta potential of –38, and an encapsulation efficiency of 96%. Microscopic evaluation confirmed the successful distribution of NPs on the walls of ASCS. Animal studies revealed that Qu/BSA NPs group exhibited a significant decrease in NLRP3, ASC, and Casp1 gene expression compared to the SCI group (p < 0.0001). The findings indicated a significant decrease in the NLRP3, ASC, and Casp1 protein level between the Qu/BSA/ASCS group and the SCI group (p < 0.0001). Moreover, treatment with ASCS containing either blank BSA (B/BSA) NPs or Qu/BSA NPs effectively promoted functional recovery via increasing the amount of nestin- and glial fibrillary acidic protein (GFAP)-positive cells in the site of injury. Notably, Qu/BSA/ASCS exhibited superior outcomes compared to B/BSA/ASCS. Overall, the combination of ASCS with the Qu delivery system presents a promising therapeutic approach for SCI by inhibiting inflammatory responses and promoting neuroregeneration, leading to the restoration of motor function in animals. This study demonstrates the potential of utilizing biomaterials and NPs to enhance the effectiveness of SCI treatment.Note: Graphic abstract was designed with Biorender (https://biorender.com/).Graphical abstract: Inflammatory responses play a crucial role in the pathophysiology of spinal cord injury (SCI) and developing new approaches to establish an anti-inflammatory environment for the promotion of neuroregeneration holds promise as a potential approach. In this study, our aim was to investigate the potential of combining an acellular spinal cord scaffold (ASCS) with quercetin-loaded bovine serum albumin (Qu/BSA) nanoparticles (NPs) for the treatment of SCI. The ASCS was prepared using physical and chemical methods, while the Qu/BSA NPs were prepared through a desolvation technique. The NPs exhibited favorable characteristics, including a mean size of 203 nm, a zeta potential of –38, and an encapsulation efficiency of 96%. Microscopic evaluation confirmed the successful distribution of NPs on the walls of ASCS. Animal studies revealed that Qu/BSA NPs group exhibited a significant decrease in NLRP3, ASC, and Casp1 gene expression compared to the SCI group (p < 0.0001). The findings indicated a significant decrease in the NLRP3, ASC, and Casp1 protein level between the Qu/BSA/ASCS group and the SCI group (p < 0.0001). Moreover, treatment with ASCS containing either blank BSA (B/BSA) NPs or Qu/BSA NPs effectively promoted functional recovery via increasing the amount of nestin- and glial fibrillary acidic protein (GFAP)-positive cells in the site of injury. Notably, Qu/BSA/ASCS exhibited superior outcomes compared to B/BSA/ASCS. Overall, the combination of ASCS with the Qu delivery system presents a promising therapeutic approach for SCI by inhibiting inflammatory responses and promoting neuroregeneration, leading to the restoration of motor function in animals. This study demonstrates the potential of utilizing biomaterials and NPs to enhance the effectiveness of SCI treatment.Note: Graphic abstract was designed with Biorender (https://biorender.com/). [ABSTRACT FROM AUTHOR]