Helicobacter pylori and gastric cancer: A potential new paradigm of 3R (remove, remodel, repair) integrated therapy based on nanomaterials

Helicobacter pylori (H. pylori) infection is the most important modifiable risk factor for gastric cancer. However, conventional antibiotic therapies face increasing challenges from antimicrobial resistance, gut microbiota dysbiosis, and mucosal damage. This review proposes a nanomaterial‑based "3R" integrated strategy – Remove H. pylori, Remodel the microenvironment, and Repair the gastrointestinal tract – as a comprehensive solution. The strategy utilizes pH/light/magnetic multi‑responsive nanomaterials for precise pathogen eradication; targets virulence factors such as VacA to reverse local immunosuppression; and simultaneously repairs the mucosal barrier while maintaining gut microbiome homeostasis. Representative nanomaterials (metal‑organic frameworks, charge‑reversal nanoparticles, nanozymes, antimicrobial peptide crystals) act through targeted bacterial killing, autophagy activation, and upregulation of tight junction proteins. This review provides a potential roadmap for system‑precision intervention beyond the traditional "sterilization‑first" paradigm.

Introduction
Gastric cancer remains a leading cause of cancer death worldwide. H. pylori infection, classified as a Class I carcinogen, significantly increases gastric cancer risk through chronic infection, immune dysregulation, and tumor microenvironment remodeling. In China, the individual infection rate is 40.66%, with family infection rates as high as 71.21%. Current treatment relies on multidrug regimens (antibiotics, proton pump inhibitors, bismuth), but faces severe challenges: rising antibiotic resistance, gut microbiota disruption, and lack of mucosal repair. This review introduces a nanomaterial‑mediated 3R integrated therapeutic paradigm to overcome these limitations.

Remove H. pylori
Nanomaterials achieve precise pathogen elimination through multiple mechanisms:

• Endogenous stimulation: pH‑responsive materials (e.g., ZAN@CS MNDs, Pd(H)@ZIF‑8) release Zn²⁺ and H₂ in gastric acid, disrupting bacterial membranes and inhibiting urease. Enzyme‑responsive systems (AP‑nanogel) enable site‑specific drug release at inflamed sites. ROS‑responsive materials (L. reuteri@HTP) degrade selectively in inflammatory environments.

• Exogenous/multimodal stimulation: Photothermal agents (GNS@Ab) convert light to heat; sonodynamic systems (Ver‑PLGA@Lec) generate ROS under ultrasound; magnetothermal materials (FeCo@G) produce local hyperthermia. Multimodal platforms (Pd(H)@ZIF‑8@AP, Fe‑HMME@DHA@MPN) combine pH, light, and ultrasound responses for enhanced efficacy.

• Targeted strategies: Ligand‑directed nanocarriers home to H. pylori surface epitopes (e.g., UreI‑targeted urea‑chitosan nanoparticles increase local amoxicillin concentration 14‑fold). Molecular targeting inhibits virulence factors (CagA, VacA) and urease. Physical targeting (light, ultrasound, magnetic fields) enables spatiotemporally controlled elimination.

• Progressive selection framework: Tier 1 – pH‑responsive monofunctional materials (most clinically mature); Tier 2 – physical sterilization materials (require device integration); Tier 3 – multimodal platforms (proof‑of‑concept for mechanistic exploration).

Remodel the Microenvironment
Nanomaterials reshape the gastric immune microenvironment through:

• Adsorbing virulence factors: Ver‑PLGA@Lecithin nanoparticles adsorb >90% of VacA, blocking its binding to integrin β1 and downregulating NLRP3/IL‑1β activation. Polydopamine‑coated ceria nanorods clear free VacA via electrostatic interactions, restoring M2 macrophage polarization.

• Activating innate immunity: Copper‑based MOFs induce immunogenic cell death, activating dendritic cells and T‑cell responses. Nanomaterials mimic pathogen‑associated molecular patterns to activate TLRs, promoting inflammatory cytokine secretion and macrophage phagocytosis.

• Promoting adaptive immunity: Self‑adjuvant lipopeptide vaccines (H. pylori10) activate DCs and TLR2/NLR/RLR pathways, inducing Th1/Th17 responses and secretory IgA antibodies, reducing colonization ~10‑fold.

• Regulating immune cells: Chiral AuNPs selectively activate macrophage autophagy and drive M2 polarization. Macrophage membrane‑coated nanoparticles trigger ROS storms and M1 polarization, bridging innate and adaptive immunity.

• Inhibiting immune evasion: Nanomaterials block CagA‑mediated PD‑L1 upregulation and counteract VacA‑induced Treg expansion.

• Activating autophagy: AP@CS@Lip@HKUST‑1 induces lysosomal acidification and LC3B conversion, clearing intracellular H. pylori. ICG@FCS generates singlet oxygen under ultrasound, inducing autophagy and enhancing intracellular bacterial clearance.

Repair the Gastrointestinal Tract
Nanomaterials promote mucosal healing and microbiota restoration through:

• Mucus barrier enhancement: Cu‑MOF@NF penetrates mucus via fucoidan modification, competitively blocks Lewis b‑binding, reduces H. pylori adhesion by 82%, and stimulates MUC5AC secretion to restore mucus thickness. ICG@FCS upregulates tight junction proteins (claudin‑1, occludin) by 2.3‑ and 1.9‑fold, reducing barrier permeability.

• Antioxidant and anti‑inflammatory mechanisms: Nanozymes (FPB‑Co‑Ch) activate SOD/CAT/POD activity to convert ROS to oxygen, inhibit VacA release, block NF‑κB signaling, and downregulate IL‑1β/IL‑6 while upregulating TGF‑β.

• Microbial community regulation: Metal nanoparticles and pH‑responsive carriers minimize off‑target effects. Nanocarriers protect probiotics against gastric acid, facilitating colonization and competitive inhibition of pathogens. Gastric‑derived Lactobacillus plantarum XB7 inhibits NF‑κB and c‑Jun pathways, reducing IL‑8 and neutrophil infiltration.

• Tissue repair and regeneration: Fu‑GaLip@KP nanocapsules restore lysosomal acidification, enhance autophagy, block CagA‑NF‑κB, reduce ROS and inflammatory factors, and reshape gut microbiota while promoting gastric epithelial morphological repair.

3R Integration Strategy
Nanomaterials achieve synergistic effects through:

• Targeted elimination: Recognition (antibody/peptide surface modification) → Capture (cationic/ligand‑mediated electrostatic adsorption) → Catalysis (ROS scavenging and inflammation suppression).

• Immune regulation and inflammation remodeling: ROS neutralization → NF‑κB/NLRP3 blockade → M1‑to‑M2 macrophage polarization ("clearance‑blocking‑reprogramming").

• Mucosal repair and microbiota protection: Pd(H)@ZIF‑8 releases H₂ and Zn²⁺ to disrupt bacterial membranes, scavenge ROS, downregulate NF‑κB, and upregulate ZO‑1/occludin‑1 while preserving intestinal α‑diversity. BiG@MC microcapsules form protective films on ulcer surfaces, downregulate inflammatory factors, and promote angiogenesis without altering gut microbiota structure.

Paradigm Shift: From Strategy Comparison to Systems‑Level Intervention
Traditional antibiotics terminate at bacterial death. Probiotic adjuncts provide passive, post‑hoc repair. The 3R strategy redefines the therapeutic endpoint from "bacterial negativity" to "gastrointestinal functional homeostasis" through:

• Temporal dimension: Sequential intervention (eradication → remodeling → repair).

• Spatial dimension: Expansion from "pathogen alone" to "pathogen‑host interface‑microenvironment" tripartite system.

• Biological dimension: Transition from exogenous drug intervention to reactivation of host intrinsic repair capacity.

Tiered prioritization framework:

• First‑line priority: Nanoplatforms with dual self‑responsive eradication and immune remodeling (e.g., AP@CS@Lip@HKUST‑1).

• Synergistic/adjunctive: VacA‑adsorbing nanomaterials (e.g., Ver‑PLGA@Lec) for patients with VacA‑high‑expressing strains or severe active gastritis.

• Reserve/exploratory: Tissue‑regenerative nanomaterials (e.g., Fu‑GaLip@KP) – evidence primarily from murine models; require large‑animal validation.

Conclusions
The 3R nanotherapeutic paradigm shifts H. pylori management from empirical antibiotic use toward precision‑integrated intervention. By integrating pathogen removal, microenvironment remodeling, and tissue repair, this approach overcomes antibiotic resistance and microbiota disruption while promoting gastrointestinal homeostasis. However, clinical translation remains early; current evidence is predominantly from cell and mouse models. Future efforts must focus on optimizing nanomaterial biocompatibility, elucidating material‑host‑pathogen interactions, and advancing preclinical validation through large‑animal studies and prospective clinical trials. Through interdisciplinary collaboration, this approach holds promise for safer and more effective H. pylori management within an integrative medical framework.

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The study was recently published in the Cancer Screening and Prevention.

Cancer Screening and Prevention (CSP) publishes high-quality research and review articles related to cancer screening and prevention. It aims to provide a platform for studies that develop innovative and creative strategies and precise models for screening, early detection, and prevention of various cancers. Studies on the integration of precision cancer prevention multiomics where cancer screening, early detection and prevention regimens can precisely reflect the risk of cancer from dissected genomic and environmental parameters are particularly welcome.

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