Arming the living drugs: nanoengineered bacteria for precision tumor theranostics

Bacteria-mediated tumor therapy exploits the innate ability of anaerobic bacteria to selectively colonize hypoxic tumor regions. However, clinical translation of this approach is hindered by three core challenges: insufficient monotherapy efficacy, the inability to non-invasively track bacterial biodistribution in vivo, and safety concerns. Nanotechnology offers solutions by enabling the construction of multifunctional nanoengineered bacteria. This review systematically summarizes six strategies for integrating nanomaterials with living bacteria-physical adsorption, covalent conjugation, bio-orthogonal chemistry, self-polymerization, biomineralization, and internalization-and critically analyzes how the interfacial properties of each strategy govern the resulting theranostic function. These nanoengineered systems address the key challenges by enabling multimodal imaging for real-time tracking, enhancing therapeutic efficacy through chemodynamic, photothermal, photodynamic, and immunotherapeutic modalities, and providing spatiotemporal control via external stimuli. We further examine the in vivo fate of these biohybrids, including immune clearance, tumor colonization, and the mechanisms for external and tumor-microenvironment-responsive activation. Safety considerations, including infection risk, cytokine release, nanomaterial immunogenicity, and regulatory requirements, are critically discussed. Finally, we outline future directions with an emphasis on adaptive coating design, hierarchical control and self-elimination strategies, and the manufacturing and standardization frameworks needed for clinical translation of this emerging class of anticancer theranostics.