Tumor tissue has different acidity compared to normal tissue. Localized drug delivery that release chemotherapeutic medications upon stimulation via pH changes is a promising strategy in cancer therapy for adjuvant therapies after surgical resection to reduce the risk of local recurrence. In this study, a mesoporous nanofibrous system with acidic pH-triggered "caps" has been for the first time developed for localized on-demand drug release to target tumor cells, without biological damage to normal cells while maintaining their structural integrity to support future tissue regeneration. Specifically, polyacrylic acid (PAA) was grafted on electrospun mesoporous silica nanofibers (MSFs) and the obtained PAA-MSFs allowed efficient drug loading at neural pH and on-demand releasing at acidic cancer subcellular compartments, based on pH-dependent electrostatic interactions associated with protonation/deprotonation of PAA. The The hybrid mesoporous nanofibers a low cytotoxicity to normal cells and a high killing efficiency to cancer cells. The system demonstrated a great potential as tumor targeting drug delivery system.