Programmable microbial therapeutics: advances in engineered bacteria for targeted in vivo delivery and precision medicine

• Bioengineered bacteria as programmable therapeutics: Recent advancements in synthetic biology and gene editing have enabled bioengineered bacteria to serve as powerful, customizable therapeutic agents, offering precision-targeted in vivo delivery and controlled release of therapeutic molecules. • Multi-mechanism approach for disease treatment: Engineered bacteria utilize multiple therapeutic mechanisms including metabolic regulation, immune modulation, and tumor-specific targeting, providing effective solutions for cancer, inflammatory diseases, and infections with minimal side effects. • Optimizing bacterial persistence and safety: New strategies, such as self-destruction circuits and immune evasion techniques, are developed to enhance the safety and persistence of bioengineered bacteria in vivo , addressing key challenges for their clinical translation and long-term therapeutic efficacy. Bioengineered bacteria have emerged as versatile, programmable platforms for in vivo drug delivery. By integrating gene editing, synthetic gene circuits, targeted surface modifications, and environment‑responsive triggers, these living vectors can home to specific tissues and dynamically release therapeutic molecules in response to local cues. Recent advances have demonstrated their potential across oncology, immunomodulation, infectious disease control, and inflammatory disorders, yet challenges in stability, biosafety, and regulatory approval remain. This review synthesizes the latest developments in programmable microbial therapeutics, focusing on engineering strategies and delivery system designs that enhance precision, efficacy, and safety. We evaluate proof‑of‑concept applications in disease models and identify critical bottlenecks hindering clinical translation, with the goal of guiding future research toward robust, personalized microbial interventions. This review centers on four main areas. First, programmable gene circuits and biosensors enable conditional drug release only when desired. Second, targeting strategies—such as adhesion molecules and microenvironmental cues—guide bacteria to disease sites. Third, delivery system designs (e.g., encapsulation and surface coating) improve bacterial survival and payload stability. Fourth, expression–optimization methods fine–tune therapeutic output levels. We also discuss biosafety measures like kill–switches and auxotrophy, and outline future directions including intelligent feedback loops, multifunctional circuits, and streamlined regulatory pathways.