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  • Review Article
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Smart closed-loop drug delivery systems

Nature Reviews Bioengineering (2025)Cite this article

Subjects

Abstract

The administration of therapeutics for long-term chronic disease management or treatment faces considerable challenges, such as the need for precise dosage control, timely delivery and adherence to medication regimens. Traditional drug delivery methods often result in suboptimal therapeutic outcomes owing to variable responses, fluctuating drug concentrations and lack of feedback from real-time monitoring. Smart closed-loop systems (CLSs) could address these limitations by integrating real-time biosensing with automated drug delivery, thereby personalizing treatments to individual needs. This Review explores the current landscape of CLSs, highlighting recent advancements in wearable and implantable technologies that facilitate continuous monitoring of biomarkers and offer responsive therapeutic interventions. We discuss the implications of device design and the trade-offs between wearable and implantable systems. In addition, we highlight the potential of artificial intelligence enhancement of CLS control algorithms by enabling systems to learn from and predict responses to achieve more effective and adaptive optimal therapies. Ultimately, this Review charts a path towards next-generation CLSs, emphasizing the integration of synthetic biology and engineered cells into implantable devices.

Key points

  • Closed-loop systems (CLSs) face barriers such as sensor stability, miniaturization of drug delivery systems and regulatory concerns, requiring extensive clinical validation for broad patient acceptance and health-care integration.

  • The trade-offs between wearable and implantable CLSs involve balancing clinical needs with treatment invasiveness and end-user engagement. Implantables offer long-term solutions whereas wearables are more suitable for short-to-mid-term treatments.

  • Artificial intelligence-driven control algorithms improve CLS performance by learning from patient data to predict disease progression and abnormalities, and optimize drug delivery, moving towards full automation with minimal human intervention.

  • The integration of engineered cells in implantable CLSs holds promise for autonomous drug delivery, although overcoming immune rejection and maintaining long-term cell viability and function in vivo remain unresolved.

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Fig. 1: Sensors in closed-loop systems.
Fig. 2: Drug delivery profiles and strategies for closed-loop systems.
Fig. 3: Advances in closed-loop systems, working principle and design consideration.
Fig. 4: Next-generation closed-loop systems.

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Acknowledgements

Support from NIAID R01AI167659, NIAID R01AI165372, NIDDK R01DK132104, NIDDK R01DK133610 (A.G.) and Houston Methodist Research Institute (A.G. and C.Y.X.C.). Further funding support from the UCSD Center of Wearable Sensors (J.W.). The authors thank V. Facciotto for the help with the conceptualization of graphics; N. Di Trani, S. Capuani, M. Farina and S. Conlan for their insightful discussions and valuable ideas; and S. P. Rodgers for help with the finalization of the manuscript.

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  1. These authors contributed equally: Marco M. Paci, Tamoghna Saha.

Authors and Affiliations

  1. Department of Nanomedicine, Houston Methodist Hospital, Houston, TX, USA

    Marco M. Paci, Corrine Ying Xuan Chua & Alessandro Grattoni

  2. College of Engineering, Swansea University, Swansea, UK

    Marco M. Paci

  3. Aiiso Yufeng Li Family Department of Chemical and Nanoengineering, University of California San Diego, La Jolla, CA, USA

    Tamoghna Saha, Omeed Djassemi & Joseph Wang

  4. Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Omeed Djassemi

  5. Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA

    Steven Wu

  6. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Corrine Ying Xuan Chua

  7. Department of Surgery, Houston Methodist Hospital, Houston, TX, USA

    Alessandro Grattoni

  8. Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA

    Alessandro Grattoni

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Contributions

A.G., M.M.P., T.S. and J.W. conceived and outlined the manuscript. All authors researched data for the article and contributed to its writing and to the discussion of its content. M.M.P. and T.S. created the figures with contribution from all co-authors. A.G., J.W. and C.Y.X.C. reviewed, edited and finalized the manuscript before submission.

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Correspondence to Joseph Wang or Alessandro Grattoni.

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We acknowledge that papers authored by scholars from historically excluded groups are systematically under-cited. Here, we have made every attempt to reference relevant papers in a manner that is equitable in terms of racial, ethnic, gender and geographical representation.

Competing interests

A.G. and C.Y.X.C. are inventors of intellectual property licensed by Continuity Biosciences. A.G. is a scientific advisor for Continuity Biosciences. J.W. is a scientific adviser for VitalTrace and Persperion Diagnostics. The other authors declare no competing interests.

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Paci, M.M., Saha, T., Djassemi, O. et al. Smart closed-loop drug delivery systems. Nat Rev Bioeng (2025). https://doi.org/10.1038/s44222-025-00328-z

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