Biologically Adaptable Quantum Dots: Intracellular in Situ Synthetic Strategy and Mechanism

ConspectusQuantum dots (QDs), a remarkable inorganic semiconductor nanocrystal capable of converting light energy into electrical, chemical, thermal, and other forms of energy, can be used to create super living systems through their fusion with cells, which hold tremendous potential for biomedical applications. Although considerable efforts have been devoted to delivering in vitro synthesized QDs into cells via endocytosis or electroporation, these approaches often suffer from poor biocompatibility, uncontrolled uptake pathways, and nonspecific intracellular interactions. Moreover, to satisfy the stringent demands of biological environments, QDs produced through conventional synthetic routes typically require extensive postsynthetic treatments, such as phase transfer into aqueous media and surface functionalization, which can irreversibly disrupt their surface structure and substantially compromise their photoluminescence quantum yield and photostability. Consequently, the exceptional optical properties of QDs are difficult to fully maintain when applied in physiological environments.Live-cell synthesis of QDs provides an innovative strategy to overcome these intrinsic limitations. By harnessing the intracellular spatiotemporally organized biochemical metabolic networks, this strategy enables the controlled synthesis of QDs while synchronously accomplishing in situ labeling. The resulting QDs are naturally coated with endogenous biomolecules and can be directed to form at specific subcellular locations, which inherently ensures high biocompatibility and precise integration with local cellular structures. This method establishes a robust foundation for in situ labeling of delicate cellular components and opens new avenues for high-fidelity acquisition of dynamic information within complex biological processes. Moreover, this flexible and universal strategy to fuse inorganic nanocrystals with live cells can endow organisms with enhanced or novel functionalities, holding significant promise for diverse applications in the fields of biomedicine and energy conversion.In this Account, we systematically summarize our efforts in the field of the live-cell synthesis of QDs. Our discussion encompasses the development of the "space-time-coupled" synthetic strategy, the elucidation of the key molecular mechanisms underlying the intracellular synthesis of QDs, and the diverse applications of this technique in pathogen detection, microvesicle labeling, site-specific protein labeling, and in vivo tumor imaging. Furthermore, inspired by the live-cell synthetic pathways, we introduce a cell-free "quasi-biosynthesis" system that enables controllable synthesis of near-infrared Ag₂Se QDs and supports surface-chemistry-based strategies for precise modulation of photoluminescence properties. Finally, we outline the key challenges and future opportunities in this field, emphasizing that the synergistic integration of genetic engineering with precision materials science will profoundly advance the intracellular synthesis of nanocrystals and unlock new possibilities in high-precision sensing, dynamic regulation, and functional augmentation of biological systems. We believe that, with a deepened understanding of the synthetic mechanisms and continued innovation in synthetic methods, the spatial precision, operational reliability, and functional integration of QDs within living systems will be significantly enhanced, thereby providing a powerful toolkit for revealing biological mechanisms and advancing precise disease diagnosis and treatment strategies.