Stable and (bio)-compatible nanofibrous matrices showing effective incorporation and release of nonsteroidal anti-inflammatory drugs (NSAIDs) hold a huge potential in tissue regeneration and wound healing. Herein, a two-step, water-based and needleless electrospinning method is used to fabricate thermally cross-linked multifunctional nanofibrous substrates from a hydrophilic cellulose derivative, i.e. carboxymethyl cellulose (CMC), and polyethylene glycol (PEG) with an in situ incorporated NSAID, diclofenac (DCF). Electrospun bi-component blend nanofibers, strongly linked together by ester bonds, with different degrees of cross-linking density are achieved by varying the concentrations of butanetetracarboxylic acid (BTCA, a green polycarboxylic cross-linker) and the sodium hypophosphite (SHP) catalyst, and the temperature. The results demonstrated that not only the dimensional stability and swelling properties could be better controlled but also the morphology, fiber diameter, surface area, pore volume, pore size, and functionality of the cross-linked nanofibers. Release kinetics of DCF from the nanofibrous substrates are controlled and prolonged up to 48 h, and the overall released mass of DCF decreased linearly with increasing cross-linking degree of BTCA and SHP. Fitting of release data using various kinetic models revealed that the release of DCF follows a non-Fickian (diffusion and erosion controlled) to Fickian mechanism (only diffusion-controlled process). Cell viability testing based on crystal violet dyeing showed that the DCF-incorporating nanofibers have excellent biocompatibility and no toxic effect on human skin fibroblast cells. Overall, the reported DCF-incorporating nanofibrous substrate demonstrates high potential to be used as a smart drug delivery system in wound healing, especially due to its noninvasive characteristics. † Electronic supplementary information (ESI) available: The information regarding the surface tension of CMC/PEG solutions admixed with different concentrations of BTCA, SEM, wettability, ATR-IR and cell viability results of electrospun samples cross-linked with different concentrations of BTCA at different temperatures are given. See Fig. 4 (A) ATR-FTIR absorption spectra of neat PEG, Na-CMC and BTCA, and non-heated CMC/PEG nanofibers with added BTCA_10%. (B) Spectrum of electrospun nanofibers cross-linked with BTCA_10% at different temperatures, (C) the absorption peak intensity ratio (1720 cm À1 / 1594 cm À1 ) of electrospun samples cross-linked with different BTCA concentrations and temperatures, (D) spectrum of pure DCF and DCF incorporated electrospun nanofibers cross-linked with different BTCA concentrations at 160 C.21294 | RSC Adv., 2019,9,[21288][21289][21290][21291][21292][21293][21294][21295][21296][21297][21298][21299][21300][21301] This journal is