1121 - Supramolecular-Engineered Biohybrid Probiotics Reprogram Gut Microenvironment for Precision Radioprotection
Presenter(s)
M. Chen1, J. Wang2,3, Z. Zhang4, and J. Lang1; 1Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China, 2School of Clinical Medicine, Southwest Medical University, Luzhou, China, 3Department of Oncology, Third People's Hospital of Yibin, Yibin, China, 4School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
Purpose/Objective(s): To overcome the clinical limitations of antioxidant-probiotic therapies in radioprotection, we develop a supramolecular bio-interface engineering strategy to construct CD44/ROS dual-responsive living nanorobots (Mix@TA-Fe/HA). These biohybrids enable precision intestinal radioprotection via stem cell niche preservation, immunometabolic reprogramming, and microbiota resetting. By addressing key challenges—including probiotic inactivation in gastric acid, ROS bursts in radiation fields, and irreversible epithelial barrier damage—this platform offers a paradigm shift in therapeutic strategies for abdominal radiotherapy.
Materials/Methods: A pH-gated supramolecular armor was engineered via Fe³?-tannic acid coordination at pH 5.0, with hyaluronic acid functionalization enhancing CD44 targeting. CRISPR-optimized WecMix01 consortia, comprising five strains including Bifidobacterium animalis WKB148, were selected via TLR2/4-NF?B reporter assays for optimal immunomodulation. A multimodal characterization platform integrated synchrotron X-ray absorption spectroscopy to resolve Fe³? coordination, in situ EPR for pH-switchable Fenton-like catalysis, and single-cell RNA-seq to identify IL-22? macrophage subsets. Dual disease models were established: miniature two-photon microscopy tracked Lgr5? stem cell dynamics in radiation injury, and metabolic cage systems quantified obesity-associated radiation syndrome in a high-fat diet model.
Results: The biohybrid platform achieved spatiotemporal precision, with 92.5 ± 3.8% gastric survival (vs. 8.7 ± 2.1% for free probiotics) and >95% intestinal payload release within 30 min. Mechanistic validation revealed three synergistic effects: (1) Stem cell niche protection: HDAC3-Notch1 activation enhanced crypt regeneration (2.8× survival in organoids), restoring villus height to 83.2 ± 6.7 µm (vs. 41.5 ± 5.2 µm in controls). (2) Immunometabolic rewiring: Single-cell analysis identified IL-22? macrophages (14.7% subset) mediating gut-liver crosstalk, reducing FITC-dextran leakage by 67%. (3) Microbial resetting: The Shannon index increased 2.1×, with butyrate production reaching 15.2 mmol/L, activating PPAR?-UCP1-driven adipocyte browning (34% volume reduction). Density functional theory calculations confirmed p-electron-mediated ROS scavenging surpassing natural SOD by 17×, while Fenton-like catalysis converted ·OH to O2 with >82% efficiency.
Conclusion: This study establishes a living-nonliving supramolecular system that overcomes the single-mechanism limitations of conventional radioprotectants through pH-gated delivery, triple-defense cascades, and cross-scale efficacy. By simultaneously addressing radiation injury and metabolic dysregulation, this approach represents a paradigm shift in fourth-generation intelligent biologics.