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Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI. • Stub1 overexpression significantly protects against spinal cord injury. • Stub1 plays a vital role in managing ER stress and autophagy flux post SCI. • Stub1 reduces ER stress-induced neuronal apoptosis by restoring the obstructed autophagy flux after SCI. • Stub1 promotes autophagic flux by activating TFEB and targeting HDAC2 for degradation. • Stub1 emerges as a promising target for neuroprotective interventions in SCI. [ABSTRACT FROM AUTHOR]

• Zein nanoparticles for sustained-release chloroquine were successfully prepared. • Zein nanoparticles reduced chloroquine toxicity through sustained release. • Chloroquine released from zein nanoparticles inhibited neuroinflammation. • Degradation products of zein nanoparticles promoted M2 microglia polarization. Inflammation is a pivotal molecular event in secondary spinal cord injury (SCI). However, chloroquine (CQ) is an anti-malarial drug with remarkable anti-inflammatory effects. Zein is a biodegradable biomaterial derived from natural-plant protein and is widely applied in drug sustained-release carriers due to its promising biocompatibility and biodegradability. In this research, we investigated the significant effects and underlying molecular mechanisms of zein nanoparticles (NPs) loaded with CQ in SCI. More importantly, we found that local delivery of Zein-CQ NPs after SCI could significantly improved functional recovery, inhibited neuronal apoptosis, alleviated neuroinflammation and enhanced M2 phenotype microglia polarization. Mechanistically, our findings further demonstrated that local administration of Zein-CQ NPs inhibited activation of the MAPK/NF-κB signaling pathway after SCI in rats. Moreover, Zein-CQ NPs reduced the release of pro-inflammatory factors and augmented the protein expression of M2 phenotype microglia in lipopolysaccharide (LPS)-stimulated BV2 cells. Our findings imply that local delivery of Zein-CQ NPs produces promising therapeutic benefits for the treatment and management of SCI. [ABSTRACT FROM AUTHOR]