Current interstitial therapies for glioblastoma can overcome the blood-brain barrier but fail to optimally release therapy at a rate that stalls cancer reoccurrence. To address this lapse, acetalated dextran (Ace-DEX) nanofibrous scaffolds were used for their unique degradation rates that translate to a broad range of drug release kinetics. A distinctive range of drug release rates was illustrated via electrospun Ace-DEX or poly(lactic acid) (PLA) scaffolds. Scaffolds composed of fast, medium, and slow degrading Ace-DEX resulted in 14.1%, 2.9%, and 1.3% paclitaxel released per day. To better understand the impact of paclitaxel release rate on interstitial therapy, two clinically relevant orthotopic glioblastoma mouse models were explored: (1) a surgical model of resection and recurrence (resection model) and (2) a distant metastasis model. The effect of unique drug release was illustrated in the resection model when a 78% long-term survival was observed with combined fast and slow release scaffolds, in comparison to a survival of 20% when the same dose is delivered at a medium release rate. In contrast, only the fast release rate scaffold displayed treatment efficacy in the distant metastasis model. Additionally, the acid-sensitive Ace-DEX scaffolds were shown to respond to the lower pH conditions associated with GBM tumors, releasing more paclitaxel in vivo when a tumor was present in contrast to nonacid sensitive PLA scaffolds. The unique range of tunable degradation and stimuli-responsive nature makes Ace-DEX a promising drug delivery platform to improve interstitial therapy for glioblastoma.