Chronic inflammation plays a side effect on tissue regeneration, greatly inhibiting the repair or regeneration of tissues. Conventional local delivery of anti-inflammation drugs through physical encapsulation into carriers face the challenges of uncontrolled release. The construction of an inflammation-responsive prodrug to release anti-inflammation drugs depending on the occurrence of inflammation to regulate chronic inflammation is of high need. Here, we construct nanofiber-based scaffolds to regulate the inflammation response of chronic inflammation during tissue regeneration. An inflammation-sensitive prodrug is synthesized by free radical polymerization of the indomethacin-containing precursor, which is prepared by the esterification of N-(2-hydroxyethyl) acrylamide with the anti-inflammation drug indomethacin. Then, anti-inflammation scaffolds are constructed by loading the prodrug in poly(ε-caprolactone)/gelatin electrospun nanofibers. Cholesterol esterase, mimicking the inflammation environment, is adopted to catalyze the hydrolysis of the ester bonds, both in the prodrug and the nanofibers matrix, leading to the generation of indomethacin and the subsequent release to the surrounding. In contrast, only a minor amount of the drug is released from the scaffold, just based on the mechanism of hydrolysis in the absence of cholesterol esterase. Furthermore, the inflammation-responsive nanofiber scaffold can effectively inhibit the cytokines secreted from RAW264.7 macrophage cells induced by lipopolysaccharide in vitro studies, highlighting the great potential of these electrospun nanofiber scaffolds to be applied for regulating the chronic inflammation in tissue regeneration.