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Chemically modified and inactivated bacteria enable intra-biofilm drug delivery and long-term immunity against implant infections

Nature Biomedical Engineering (2026)Cite this article

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Abstract

Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a ‘trick-bacteria-with-bacteria’ strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.

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Fig. 1: Schematic illustration of the tricker bacteria delivering antibiotics into the biofilm and impacting the antibacterial immune responses.
Fig. 2: Characterization of the tricker bacteria.
Fig. 3: Mechanism of the intra-biofilm delivery of antibiotics by the tricker bacteria.
Fig. 4: Antibiotic-loaded tricker bacteria reverses the immunosuppressive phenotype of BAMs.
Fig. 5: Untargeted metabolomics profiling of BIO-CM.
Fig. 6: Topical application of drug-loaded tricker bacteria in established subcutaneous implant biofilm infections and its efficacy to resist rechallenged bacteria.
Fig. 7: Modified bacterial therapy enhances the antibacterial effect of vancomycin in bone implant infections and triggers long-term immune responses to prevent infection relapse.

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Acknowledgements

We acknowledge financial support from the National Key R&D Program of China (2022YFB3804500; to H.L.), Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch (JCYJ-SHFY-2022-003; to H.L.), National Natural Science Foundation of China (52372276, 22335006 and 82302717; to H.L. and C.Y.), Youth Innovation Promotion Association CAS (2023262; to H.L.), Young Elite Scientists Sponsorship Program by CAST (YESS20210149; to H.L.), Shanghai Science and Technology Committee Rising-Star Program (22QA1410200; to H.L.), China Postdoctoral Science Foundation (2023M732310; to C.Y.), Shanghai Sailing Program (23YF1432200; to C.Y.), Natural Science Foundation of Shanghai (23ZR1472300; to H.L.), Harvard/Brigham Health and Technology Innovation Fund (2023A004452; to W.T.), Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (113548; to W.T.), Department Basic Scientist Grant (2420 BPA075; to W.T.), Nanotechnology Foundation (2022A002721; to W.T.), and Distinguished Chair Professorship Foundation (018129; to W.T.).

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Authors and Affiliations

  1. Department of Orthopaedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chuang Yang

  2. Center for Nanomedicine and Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Qimanguli Saiding, Wei Chen, Soohwan An, Senfeng Zhao, Muhammad Muzamil Khan, Na Kong & Wei Tao

  3. Department of Electrical Engineering, City University of Hong Kong, Hong Kong, China

    Min Ge

  4. Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai, China

    Jianlin Shi & Han Lin

  5. Shanghai Tenth People’s Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, China

    Jianlin Shi & Han Lin

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Contributions

C.Y., M.G., H.L. and W.T. conceived of the study. C.Y., M.G., H.L. and W.T. designed the experiments. C.Y., M.G., H.L., Q.S., W.C., S.A., M.M.K., N.K., S.Z. and J.S. performed the experiments, discussed and analysed the data or provided essential experimental resources. C.Y., M.G., H.L. and W.T. wrote the paper, and the paper was revised by all the authors.

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Correspondence to Min Ge, Han Lin or Wei Tao.

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Extended data

Extended Data Fig. 1 The penetration of modified S. aureus into S. aureus biofilm.

S. aureus-eGFP biofilm (green) was treated with modified S. aureus-mcherry (red). The fluorescent images showed the penetration process of the tricker S. aureus. The experiments were repeated independently at least three times with similar results.

Extended Data Fig. 2 The penetration of modified E.coli into E.coli biofilm.

E. coli-sfgfp biofilm (green) was treated with modified E. coli-mcherry (red). The fluorescent images showed the penetration process of the tricker E. coli. The experiments were repeated independently at least three times with similar results.

Extended Data Fig. 3 The penetration of modified E.coli into S. aureus biofilm.

S. aureus-eGFP biofilm (green) was treated with modified E. coli-mcherry (red). The experiments were repeated independently at least three times with similar results.

Extended Data Fig. 4 The penetration of modified S. aureus into E.coli biofilm.

E. coli-sfgfp biofilm (green) was treated with modified S. aureus-mcherry (red). The experiments were repeated independently at least three times with similar results.

Extended Data Fig. 5 Protein bands of live and tricker bacteria.

The protein expression profile of live and tricker bacteria was determined by Coomassie Brilliant Blue staining. The experiments were repeated independently at least three times with similar results.

Source data

Extended Data Fig. 6 Penetration effect of tricker bacteria into polymicrobial biofilms.

a, Schematic of polymicrobial biofilms consists of S.aureus, E.coli and C.albicans. b, Low and high magnification of SEM images of the polymicrobial biofilms. S. aureus, E.coli and C.albicans are pseudo-colored with red, purple and brown, respectively. c, Flow cytometry plots of dislodged single-species biofilm or polymicrobial biofilms. d, Representative three-dimensional fluorescent images of biofilms (green) before and after incubation with PI-stained Van@Tr-S.a., Cip@Tr-E.c. or Flu@Tr-C.a. (red). For b, d, the experiments were repeated independently at least three times with similar results.

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Unprocessed Coomassie Brilliant Blue staining gels.

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Yang, C., Saiding, Q., Chen, W. et al. Chemically modified and inactivated bacteria enable intra-biofilm drug delivery and long-term immunity against implant infections. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-025-01600-8

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  • DOI: https://doi.org/10.1038/s41551-025-01600-8

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