The limited drug penetration and robust bacteria-mediated drug inactivation in pancreatic cancer result in the failure of chemotherapy. To fight against these issues, a dual-cascade responsive nanoparticle (sNP@G/IR) that can sequentially trigger deep penetration, killing of intratumor bacteria, and controlled release of chemo-drug, is reported. sNP@G/IR consists of a hyaluronic acid (HA) shell and glutathione (GSH)-responsive polymer-core (NP@G/IR), that encapsulates gemcitabine (Gem) and photothermal agent (IR1048). The polymer core, as an antibiotic alternative, is tailored to exert optimal antibacterial activity and selectivity. sNP@G/IR actively homes in on the tumor due to the CD44 targeting of the HA shell, which is subsequently degraded by the hyaluronidase in the extracellular matrix. The resultant NP@G/IR in decreased size and reversed charge facilitates deep tumor penetration. After cellular endocytosis, the exposed guanidine on NP@G/IR kills intracellular bacteria through disrupting cell membranes. Intracellular GSH further triggers the controlled release of the cargo. Thus, the protected Gem eventually induces cell apoptosis. Under laser irradiation, the hyperthermia of IR1048 helps further elimination of tumors and bacteria. Moreover, sNP@G/IR activates immune response, thereby reinforcing anticancer capacity. Therefore, this dual-cascade responsive sNP@G/IR eliminates tumor-resident intracellular bacteria and augments drug delivery efficacy, providing a new avenue for improving cancer therapy.