Zn²⁺-based nanoparticles eliminate intratumoral bacteria to synergistically enhance gemcitabine efficacy in pancreatic cancer therapy

Gemcitabine (Gem) is the gold-standard chemotherapeutic drug for pancreatic cancer therapy in clinic. However, intratumoral bacteria can metabolize Gem into an inactive form, leading to Gem resistance. To address this challenge, Zn²⁺-containing nanoparticles (ZGP NPs) are used to eliminate intracellular bacteria to enhance the therapeutic efficacy of Gem in pancreatic therapy. ZGP NPs are prepared via a facile one-pot method using Zn²⁺, epigallocatechin gallate (EGCG), and polyethylene glycol (PEG), which prevents metal ion chelation by proteins and ensures antibacterial activity. Leveraging the pH-responsive disassembly of metal-phenolic networks, ZGP NPs can be degraded in acidic lysosomes after cellular uptake, releasing Zn²⁺ to eliminate intracellular bacteria and thereby protecting Gem from bacteria-mediated inactivation. Moreover, the elimination of intratumoral bacteria enhances immunotherapy. The delivery of Zn²⁺ via ZGP NPs presents a promising strategy to eliminate intratumoral bacteria to overcome Gem resistance in pancreatic cancer therapy.