Plant-bacteria hybrid nanovesicles for targeted sonodynamic therapy: A microbiome-friendly precision strike against...

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.