2D heterostructures at the biointerface: From biosensing to theranostics and tissue engineering

Two-dimensional (2D) heterostructures provide biointerfaces in which electronic, chemical, optical, and mechanical functions can be coordinated through engineered junctions beyond the capabilities of individual constituents. This review critically examines inorganic and hybrid 2D heterostructures that directly interact with biomolecules, cells, tissues, or biofluids across biosensing, wearable and implantable bioelectronics, theranostics, drug and gene delivery, biomedical imaging, antimicrobial systems, and tissue engineering. A design-centric architecture-interface-biofunction framework connects vertical, lateral, and mixed-dimensional configurations with band alignment, interfacial charge transfer, defect and vacancy chemistry, interlayer coupling, twist and strain, surface functionalization, and biofluid-induced transformations. Comparative evidence indicates that MXene-based 2D-2D heterostructures are among the most versatile platforms for integrating sensing, therapeutic, and bioelectronic functions, whereas TMD-, MOF-, LDH-, graphene-, and carbon nitride-based systems provide complementary advantages for specific applications. Rational interface engineering can enhance signal amplification, bioactivity, photothermal conversion, reactive oxygen species generation, cargo loading, and multifunctionality. However, definitive cross-platform comparisons remain limited by substantial variation in material composition, fabrication route, biological model, exposure conditions, and performance reporting. Translation is further constrained by interfacial contamination, variable alignment and contact quality, oxidation, restacking, biofouling, structural degradation in physiological media, limited reproducibility, and insufficient knowledge of biodistribution, clearance, and degradation products. Future progress requires scalable, low-contamination fabrication; mechanism-based evaluation in target biofluids and relevant in vivo models; standardized reporting of performance, stability, fouling, toxicity, and reproducibility; and complementary characterization before and after biological exposure. Safety-by-design and stability-by-design strategies, interlaboratory validation, reference materials, and regulatory assessment aligned with the intended mode of action will be essential for advancing 2D heterostructure biointerfaces from laboratory demonstrations toward reliable biomedical implementation.