Plant-Bacteria Hybrid Nanovesicles for Targeted Sonodynamic Therapy: A Microbiome-Friendly Precision Strike against H. pylori Infections

Rising antibiotic resistance and adverse effects on commensal gut microbiota severely compromise conventional antibiotic therapies for Helicobacter pylori infection. Sonodynamic therapy (SDT), which employs low-intensity ultrasound to activate sonosensitizers for localized generation of cytotoxic reactive oxygen species (ROS), presents a promising non-antibiotic alternative with minimal resistance development risk. However, the efficacy of SDT is inherently constrained by the short diffusion radius and lifetime of ROS. Herein, we developed a homologous-targeting biomimetic sonosensitizer platform to overcome this limitation: hybrid membrane nanovesicles (TNVs-DMVs) engineered from turmeric plant-derived exosome-like nanovesicles (TNVs) and H. pylori -derived double membrane vesicles (DMVs). TNVs contain sonosensitizer curcumin and improve its solubility, yet SDT efficacy against H. pylori is limited. The DMVs endow TNVs-DMVs with intrinsic homologous targeting capability towards H. pylori , significantly enhancing the intracellular delivery of curcumin and subsequent ROS generation within bacterial cells. As a result, TNVs-DMVs achieved potent eradication of H. pylori in both acidic and neutral conditions without inducing detectable resistance. Moreover, TNVs-DMVs exhibited superior mucus penetration compared to TNVs alone, enabling effective elimination of H. pylori and its biofilms residing within the protective gastric mucus layer. In an H. pylori -infected mouse model, TNVs-DMVs mediated SDT demonstrated efficacy surpassing free TNVs and comparable to standard triple antibiotic therapy. Importantly, unlike triple therapy which depletes commensal flora, TNVs-DMVs treatment not only preserves intestinal microbiota homeostasis but also significantly increases populations of beneficial bacteria. This rationally designed TNVs-DMVs platform represents a transformative therapeutic modality, offering resistance-free eradication of H. pylori while maintaining microbiome health, distinct from conventional antibiotics.