This article systematically reviews the critical role of biomaterials in the delivery of living therapeutics, including mammalian cells, microbes, and viruses. It focuses on three major challenges—targeting, dose control, and stability—and proposes innovative solutions based on materials science and synthetic biology.
Literature Overview
The article 'Delivering living medicines with biomaterials,' published in Nature Reviews Materials, reviews and summarizes the current state of engineered therapeutic living cells as novel drugs through genetic programming. The article systematically analyzes the delivery challenges faced by three types of living therapeutics—mammalian cells, microbial cells, and viruses—during clinical translation, including insufficient targeting, difficulties in dose control, and poor in vivo stability. The authors further review successful applications of existing biomaterial strategies in traditional drug delivery and explore how these can be adapted to meet the unique needs of living medicines, proposing feasible pathways for spatial control, temporal regulation, and immune evasion through material design. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Living medicines represent an emerging therapeutic modality that leverages genetically engineered living cells (e.g., T cells, bacteria, yeast) or viruses as therapeutic carriers, enabling them to sense environments, respond to stimuli, synthesize therapeutic molecules, or target diseased sites. Compared to traditional small-molecule or protein drugs, living medicines offer advantages such as dynamic regulation, local amplification, and sustained secretion, showing promise in cancer immunotherapy, metabolic disease regulation, and microbiome editing. However, their delivery faces unique challenges: first, cells must maintain viability and function, avoiding death or inactivation during delivery; second, living medicines may proliferate uncontrollably in vivo, triggering cytokine release syndrome or immune toxicity; third, the host immune system can rapidly clear exogenous cells or viruses, limiting their persistence. Additionally, different types of living medicines have distinct characteristics: CAR-T cells, while highly effective against tumors, struggle to infiltrate solid tumors and may cause off-target toxicity; engineered bacteria can colonize specific microenvironments (e.g., gut or tumor) but risk systemic spread; viral vectors efficiently transduce cells but are limited by pre-existing immunity and rapid clearance. Current research aims to develop novel delivery systems to overcome these bottlenecks, and biomaterials—due to their tunable physicochemical properties, biocompatibility, and multifunctional potential—have emerged as an ideal platform for addressing the challenges of living medicine delivery. For example, hydrogels can provide protective microenvironments, microneedles enable minimally invasive local delivery, and surface modifications can enhance targeting and reduce immunogenicity. This study focuses on transferring traditional drug delivery experience to the field of living medicines and proposes future directions in material-cell co-design, offering significant guidance.
Research Methods and Experiments
This article employs a review-based methodology to systematically summarize recent key advances in the field of living medicine delivery. The authors first classify and introduce the physical properties, clinical applications, and representative products of three major types of living medicines—mammalian cells, microbial cells, and viruses—and summarize their common and specific delivery challenges. Subsequently, the article deeply analyzes delivery barriers from three dimensions—'targeting,' 'effective dose,' and 'stability'—elucidating the core issues with specific clinical examples (e.g., CAR-T cell lung sequestration, acid inactivation of engineered bacteria, pre-existing immunity against AAV).
In the biomaterials strategies section, the authors compare locally established delivery systems in traditional drug delivery (e.g., Gliadel sustained-release wafers, Retisert intraocular implants) and targeted ligand conjugation techniques (e.g., antibody-drug conjugates), systematically summarizing the adaptation progress of these strategies for living medicines. Particular emphasis is placed on methods such as hydrogel encapsulation, microneedle patches, surface functionalization (e.g., biotin-streptavidin, polydopamine modification), and genetic engineering-based anchoring, which enhance cell retention, controlled release, and targeting. The article also summarizes the potential of stimulus-responsive materials (e.g., pH-, enzyme-responsive) in on-demand activation of living medicines and highlights the importance of dynamic material-cell interaction design.Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically establishes a framework for living medicine delivery, clarifying the central value of biomaterials in overcoming delivery bottlenecks. By drawing on traditional drug delivery experience and integrating the unique characteristics of living systems, the authors provide co-design strategies for materials scientists and synthetic biologists. For example, coupling gene circuits with material responsiveness could enable closed-loop 'sense-response-release' regulation, enhancing therapeutic precision.
Looking ahead, living medicine delivery systems must evolve toward intelligent, personalized, and clinically translatable solutions. On one hand, safer, degradable, and low-immunogenicity materials need to be developed; on the other, efficacy validation in complex disease models must be strengthened, alongside the establishment of standardized quality control systems. Moreover, balancing the therapeutic benefits of engineering enhancements with potential risks (e.g., genomic integration, long-term colonization) requires further investigation. This review provides a vital theoretical foundation and technical roadmap for the clinical translation of next-generation living medicines.
Conclusion
This article comprehensively reviews the frontier advances and key challenges of biomaterials in living medicine delivery. Although living medicines, as an emerging therapeutic modality, possess dynamic regulatory capabilities unattainable by traditional drugs, their clinical applications are limited by issues such as delivery efficiency, safety, and stability. Biomaterials have become essential tools for overcoming these obstacles by providing physical protection, enabling targeted modification, controlling release kinetics, and co-delivering auxiliary factors. The article systematically summarizes various strategies—including hydrogel encapsulation, microneedle delivery, surface functionalization, and stimulus-responsive materials—and their applications in delivering mammalian cells, microbes, and viruses, emphasizing the importance of synergistic design between materials and living systems. In the future, integrating smart gene circuits from synthetic biology with responsive advanced materials may enable on-demand activation and self-regulated precision therapy. However, clinical translation still faces challenges in scalable production, long-term biosafety, and immunogenicity management. This review offers systematic strategic guidance and research directions for advancing living medicines from the laboratory to the clinic.
