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[Display omitted] • PLGA-SH nanofibers were conjugated with SH-β-CD containing DEX and RVC. • PLGA-CD-DEX-RVC nanofibers were transplanted into the sciatic nerve in CCI rats. • PLGA-CD-DEX-RVC nanofibers can restrict drugs flow to motor nerves. • PLGA-CD-DEX-RVC nanofibers can relieve pain for extended periods. • PLGA-CD-DEX-RVC nanofibers can serve as a useful treatment for neuropathic pain. To treat neuropathic pain, dexamethasone (DEX, an anti-inflammatory agent) and ropivacaine (RVC, a local anesthetic) are injected into the epidural space of the patient's spine in clinics. This combinatorial drug treatment is short-acting and subjected to uncontrolled drug flow to the motor nerve. To overcome these limitations, we developed thiolate poly(lactic-co-glycolic acid) (PLGA-SH) nanofibers conjugated with mono-(6-mercapto-6-deoxy)-β-cyclodextrin (SH-β-CD) containing DEX and RVC. The anti-inflammatory effect in the PGLA-CD-DEX-RVC nanofibers was assessed using bone marrow-derived macrophages (BMMs) in vitro. We injured the sciatic nerve in Sprague Dawley (SD) rats to create a Chronic constriction injury (CCI) model for an in vivo assessment. Neuropathic pain was evaluated by testing the cold allodynia response, and by Immunofluorescence (IF) staining of transient receptor potential vanilloid 1 (TRPV1, a nociceptor marker) and ionized calcium-binding adaptor molecule 1 (iba1, a microglia marker). In this study, the synthesized PLGA-CD-DEX-RVC nanofibers sustainably released RVC and DEX for more than 48 h. The PLGA-CD-DEX-RVC nanofibers suppressed polarized M1 macrophages and increased polarized M2 macrophages. The allodynia cold sensitivity was consistently relieved in the PLGA-CD-DEX-RVC group for 14 days. Moreover, the expressions of the TRPV1 and iba1 were remarkably reduced in the PLGA-CD-DEX-RVC group on day 14. PLGA-CD-DEX-RVC nanofibers can restrict drugs flow to motor nerves and of relieving pain for extended periods. We suggest that PLGA-CD-DEX-RVC nanofibers can serve as a useful treatment for neuropathic pain in clinics. [ABSTRACT FROM AUTHOR]