Cellular senescence is described as an irreversible cessation of cell division triggered by intrinsic and extrinsic stressors. Although senescent cells no longer replicate, they remain metabolically active and acquire distinct phenotypic and functional changes. A central feature of senescence is resistance to apoptotic signals, permitting longevity of these cells in tissues. Senescent cells also adopt a senescence-associated secretory phenotype (SASP), secreting a complex mixture of cytokines, growth factors, proteases and other bioactive molecules that influence both cell-intrinsic processes and the surrounding microenvironment.
The SASP can modify neighboring cells and tissue architecture, propagating deleterious effects beyond the initially affected cells. Because of these secretory changes and persistent viability, senescent cells are considered active drivers of tissue dysfunction in aging rather than passive bystanders.
The prevalence of senescent cells increases with chronological age, but the proportion is variable across species, tissues and activity levels. Reported estimates range from approximately 1% to 15% of cells in some contexts. This accumulation correlates with age-related pathologies and contributes to morbidity associated with aging. The variable burden highlights that senescence is heterogeneous and context-dependent, affecting interpretation of interventions and the design of targeted therapies.
Beyond physiological aging, cellular senescence is commonly induced by cancer treatments including radiotherapy and chemotherapy. Therapy-induced senescence can have complex clinical consequences: while it may halt proliferation of malignant cells acutely, the persistence of senescent tumor or stromal cells and their SASP may promote a microenvironment conducive to tumor progression, metastasis, and recurrence. Therefore, senescence induced by cancer therapy represents a double-edged sword and a potential target for adjunctive interventions aimed at removing or modulating senescent cells after cytotoxic treatments.
Given the pathogenic role of accumulated senescent cells and their SASP, therapeutic strategies that selectively eliminate senescent cells—known as senolytic therapies—have attracted increasing research interest. The objective is to reduce the burden of senescent cells and ameliorate downstream tissue dysfunction.
However, many candidate senolytic agents in free form face pharmacological limitations. Challenges include poor aqueous solubility, instability in biological environments, limited systemic bioavailability, uncontrolled biodistribution and off-target toxicity. These factors can reduce efficacy and increase adverse effects, complicating translation from preclinical models to clinical use.
To address shortcomings of free therapeutics, nano-drug delivery systems have been engineered to enhance key pharmacological properties. Nanoparticles can improve solubility and stability of otherwise problematic compounds, protect payloads from premature degradation, and modify pharmacokinetics to increase effective exposure at target sites.
Precise control over nanoparticle size, surface properties and uniformity enables design for targeted distribution, potentially increasing therapeutic precision and reducing off-target effects. Nanocarriers also offer opportunities for surface functionalization to engage specific receptors or microenvironmental features associated with senescent cells, and for controlled or stimulus-responsive release of senolytic agents.
Collectively, these features can overcome poor bioavailability and uncontrolled biodistribution that limit many conventional senotherapeutics.
Although nanomedicine has seen extensive development and clinical translation in oncology, its specific application to mitigate cellular senescence remains comparatively underexplored. Existing nanoparticle platforms have been used broadly to improve delivery of therapeutics in diverse disease areas, demonstrating proof-of-concept that nanocarriers can enhance solubility, stability and targeting. In the context of senescence research, studies to date are fewer and disparate; this review consolidates available reports using nanoparticle-based delivery systems applied to senescent cells or senolytic strategies.
The collected literature emphasizes the conceptual alignment between the needs of senescence-targeting therapies (targeting, reduced off-target toxicity, improved pharmacokinetics) and the strengths of nanoparticle platforms. However, the review notes that comprehensive preclinical and translational exploration specifically focused on senescence is still limited compared with cancer-focused nanomedicine efforts.
This review identifies a gap between advances in nanomedicine and their application to cellular senescence and senotherapeutics. While nano-drug delivery systems address many pharmacological barriers encountered by free senolytic agents, research directly applying these systems to senescence biology is not yet fully developed.
Future work should consolidate mechanistic insights into senescent cell markers and SASP features that could serve as targeting handles, while systematically evaluating nanoparticle platforms for safety, biodistribution, and efficacy in removing or modulating senescent cells. Translational efforts will need to consider heterogeneity in senescent cell burden across tissues and species, and therapy-induced senescence in oncology contexts.
By synthesizing current knowledge of cellular senescence, the pathological roles of SASP, and the potential of nanomedicine, this review aims to stimulate focused research that leverages nanoparticle delivery systems to enhance senolytic strategies and close an important gap in aging science.