Dissecting oral premalignant carcinogenesis: spatial omics mechanisms and nanomedicine-driven therapeutic innovation

Oral potentially malignant disorder (OPMD) remains a critical clinical challenge for cancer interception. However, the progression of OPMD toward oral squamous cell carcinoma (OSCC) is driven by profound cellular heterogeneity and dynamic microenvironmental remodeling. The mechanisms underlying these processes are not yet fully understood. Recent advancements in single-cell and spatial omics have facilitated high-resolution decoding of the precancerous landscape, unveiling multistep epithelial cell plasticity, fibroblast heterogeneity with extracellular matrix remodeling, immune suppression, and inflammatory reprogramming, as well as coupled metabolic and redox alterations that govern malignant transformation. These insights into the cellular mechanisms have led to a paradigm shift in the understanding of OPMD, reclassifying it as an ecosystem-level disease rather than a purely epithelial pathology. Nanomedicine is a potent platform for translating mechanistic knowledge into precision diagnostics and interventions at the precancerous stage. Nanomaterial-based strategies have been demonstrated to facilitate several critical processes, including enabling early lesion visualization and risk stratification, immune microenvironment reactivation, anti-fibrotic and anti-inflammatory remodeling, and targeted regulation of metabolic and oxidative stress pathways. A mounting body of evidence from preclinical and clinical studies lends support to the notion that nanotechnology-assisted early detection, microenvironmental reprogramming, and the interception of malignant transformation across oral and other precancerous conditions are indeed feasible. This review integrates single-cell-resolved mechanisms of OPMD progression with state-of-the-art nanomedicine-based diagnostic and therapeutic strategies, highlighting convergent biological axes and translational opportunities. By integrating single-cell biology with nanotechnology-driven precision medicine, this work is expected to improve the development of a nanomedicine framework for early cancer detection and treatment and outline future directions and challenges toward clinical implementation.