Nanoprodrug targeting tumor-associated intracellular bacteria enhances colorectal cancer immunotherapy

  • J Control Release. 2025 Dec 6:390:114512. doi: 10.1016/j.jconrel.2025.114512.
Yunjian Yu  1 ,  Yuanchu Jin  2 ,  Yong Zhou  2 ,  Zhuoyan Cui  2 ,  Youtao Xin  2 ,  Hongyu Liu  2 ,  Jingwen Zhao  3 ,  Mahmoud Elsabahy  4 ,  Meihui Su  2 ,  Hui Gao  5
Affiliations
  • 1. State Key Laboratory of Advanced Separation Membrane Materials & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, PR China; Cangzhou Institute of Tiangong University, Cangzhou 061000, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Advanced Separation Membrane Materials & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, PR China; Cangzhou Institute of Tiangong University, Cangzhou 061000, China.
  • 3. Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 4. School of Biotechnology, Badr University in Cairo, Badr City, Cairo 11829, Egypt.
  • 5. State Key Laboratory of Advanced Separation Membrane Materials & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, PR China; Cangzhou Institute of Tiangong University, Cangzhou 061000, China. Electronic address: [email protected].
PMID: 41360332 DOI: 10.1016/j.jconrel.2025.114512
Abstract

The tumor-associated intracellular microbiota influences Cancer progression by fostering an immunosuppressive tumor microenvironment. Targeting pro-tumor intracellular bacteria may represent a promising strategy for Cancer Immunotherapy. Herein, we reveal that Fusobacterium nucleatum (F. nucleatum) is preferentially enriched within M2-polarized macrophages in both human colorectal Cancer (CRC) specimens and cellular models. Notably, its intracellular presence correlates significantly with reduced CD8+ T cell infiltration, highlighting its immunosuppressive function. To disarm this microbial shield, we develop infection-specific ciprofloxacin (CIP) prodrug nanoparticles (MTCP-NPs) conjugated to an M2 macrophage-targeting peptide (IL4Rpep-1) via a Cathepsin B (CTSB)-cleavable linker (FRRG) to selectively kill intramacrophage F. nucleatum. MTCP-NPs undergo IL4 receptor-mediated endocytosis in F. nucleatum-infected macrophages, where intracellular CTSB triggers CIP release to eliminate F. nucleatum and suppress indoleamine 2,3-dioxygenase (IDO) secretion. In F. nucleatum-infected CRC models, MTCP-NPs clear intracellular bacteria, alleviate immunosuppression by downregulating IDO and reducing MDSCs to mobilize CD8+ T cell immunity. Furthermore, this treatment modulates the gut microbiota by reprogramming tryptophan metabolism. When combined with anti-PD-L1 therapy, MTCP-NPs amplify anti-tumor efficacy and prolong survival while promoting the generation of memory-like T cells associated with sustained immune responses. This strategy establishes a unique microbiome-immunotherapy framework by targeting tumor-associated intracellular bacteria to unleash T cell responses.

Keywords
Fusobacterium nucleatum; Gut microbiota; Immunotherapy; Intracellular bacteria; Prodrug.
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