Multidimensional Regulatory Network of Cellular Senescence: From Mechanisms to Theranostics.
TL;DR
This review systematically maps the molecular architecture of the senescent-cell heterogeneity, off-target toxicity, and the lack of standardized biomarkers, and provides a framework for developing precision strategies to detect, modulate, or eliminate senescent cells in a context-appropriate manner.
Abstract
Cellular senescence is orchestrated by a complex and multidimensional regulatory network, whose functional outputs shift dynamically with disease stage and tissue context. This review systematically maps the molecular architecture of this network. The network encompasses the p53/p21 and p16/RB axes, mitochondrial stress pathways, and the cGAS-STING and mTOR-driven SASP programs. In parallel, the review traces how these mechanisms are rewired across a spectrum of pathological contexts, including cancer, metabolic and skeletal disorders, and organ-specific degenerative diseases. Building on this mechanistic foundation, we highlight theranostic innovations that integrate detection with intervention. These include enzyme-activatable prodrugs and probes that exploit senescence-associated markers such as SA-β-gal, enabling simultaneous imaging and cell clearance. Other examples are smart nanocarriers, which achieve spatiotemporally controlled drug delivery, and engineered immune cells, which restore immunosurveillance against senescent cells. Additionally, we discuss emerging platforms for dynamic quantification of senescent burden in vivo, including molecular imaging probes and liquid biopsy signatures. Despite promising preclinical progress, clinical translation remains limited by senescent-cell heterogeneity, off-target toxicity, and the lack of standardized biomarkers. By integrating mechanistic insights with theranostic design principles, this review provides a framework for developing precision strategies to detect, modulate, or eliminate senescent cells in a context-appropriate manner.