The drug discovery and therapeutic nano-strategies targeting cellular senescence

Abstract

Cellular senescence is a primary driver of aging, where damaged or senescent cells (SnCs) continuously accumulate in the body, altering the local tissue environment and causing various pathologies in different organs or tissues, offering brand-new diagnostic and therapeutic possibilities for aging-related disease. This review begins by discussing the multiple molecular mechanisms of cellular senescence. We mainly focus on the therapeutic strategies and their clinical applications targeting cellular senescence, where senolytic and senomorphic drugs are currently two main categories of anti-aging therapies. Besides, nicotinamide adenine dinucleotide (NAD⁺) enhancers or multiple therapies for anti-inflammatory and immunomodulation also hold great promise. Crucially, we highlight the design principles and formulation strategies on engineered nanotechnology-based drug delivery system (NDDS) targeting SnCs, including combination therapies and drug loading, delivery routes and bio-distribution, targeted therapy and precision medicine as well as stimuli-responsive drug release. Subsequently, we comprehensively analyze the therapeutic nano-strategies for neurodegenerative diseases, cardiovascular diseases, bone and joint diseases, fibrosis disease, cancer, and other aging-related diseases targeting cellular senescence. Finally, we propose the strength, weakness, opportunity and threat (SWOT) analysis and summarize the future development directions of the therapeutic nano-strategies targeting manipulating SnCs and treating aging related diseases, thereby paving the way for innovative and effective approaches for aging-related disease management.

Graphical abstract

Design strategies for drug delivery systems targeting cellular senescence. Figure created with BioRender.com.

1. Introduction

Medical interventions targeting the key factors of senescence are emerging as potential strategies for the treatment of age-related diseases and to enhance quality of life for residents. Notably, cellular senescence is a primary driver of aging, where damaged or senescent cells (SnCs) continuously accumulate in the body, altering the local tissue environment and causing various pathologies in different organs or tissues [1,2].

In 1961, Hayflick et al. first observed that normal human fibroblasts have a finite proliferative capacity or replicative potential after certain passages, designating a phenomenon known as “cellular senescence” [44] (Fig. 1). Unlike quiescence, senescence is traditionally believed to be irreversible through external interventions such as removing contact inhibition or adding nutrients. Cellular senescence always results from a range of inter-dependent mechanisms including telomere attrition, DNA damage, epigenetic erosion, metabolic imbalance, and loss of proteostasis. Different from terminal differentiation, it triggers stress response programs, characterized by a stable state of cell cycle arrest, morphological and metabolic changes, cyclin-dependent kinase (CDK) inhibitors of p16 and p21 overexpression, elevated activity of senescence-associated β-galactosidase (SA-β-gal), lipofuscin accumulation [[45], [46], [47], [48], [49]]. It also features with the continuous production of secretory factors, including cytokines (e.g. interleukin [IL]-6, IL-8, etc.), chemokines (e.g. C-C motif chemokine ligand [CCL]-2, CXCL2, etc.), growth factors (e.g. epidermal growth factor [EGF], vascular endothelial growth factor [VEGF], etc.), proteases (e.g. matrix metalloproteinases [MMPs] etc.) and some extracellular vesicles (particularly exosomes), collectively termed as senescence-associated secretory phenotypes (SASPs) [[50], [51], [52], [53], [54]]. In general, transient senescence typically prevents the proliferation of damaged cells by causing cell-cycle arrest at the G1 phase or possibly the G2 phase, defending against various intracellular and extracellular stresses. However, persistent senescence or the long-term accumulation of SnCs in organs can be maladaptive, leading to chronic inflammation and tissue dysfunction, and finally trigger multiple age-related diseases, including neurodegenerative disorders (NDs), cardiovascular diseases (CVD), bone and joint diseases, cancer, and fibrotic diseases [[55], [56], [57], [58], [59]]. What's worse, immunosenescence is marked by a decline in immune function and an increase in inflammatory factors, primarily manifested as a reduced immune response to both endogenous and exogenous antigens, thus reducing an individual's ability to resist internal/external stimuli and clear SnCs. These determinants of cellular senescence are interconnected and cross-talked with other dysregulated cellular mechanisms during aging (e.g., metabolism), posing challenges to precisely delineating their distinct contributions to senescence [[60], [61], [62], [63]]. A better understanding of the cellular and molecular mechanisms of tissue and organism degeneration and ageing-associated diseases is crucial for developing targeted drug therapies to ameliorate these diseases (see Fig. 2).

Fig. 1.

Development of SnCs-related molecular mechanisms and therapeutic strategies. Timeline of the historical milestone for the discovery of SnCs-related molecular mechanisms and therapeutic strategies (A) and statistical analysis on their biomedical applications (B). Figure created with BioRender.com.

Fig. 2.

Mechanisms of cellular senescence. Figure created with BioRender.com.

Considering the multifaceted role of cellular senescence in various diseases, it gradually becomes a promising intervention target. In this review, we first provide a comprehensive analysis of the multiple molecular mechanisms of cellular senescence. Subsequently, we highlight the therapeutic strategies targeting cellular senescence and systematically summarize the cutting-edge achievements in the field of anti-aging agents, where senolytic and senomorphic drugs are currently two main categories of anti-aging therapies. Besides, gene and epigenetic regulation, nicotinamide adenine dinucleotide (NAD⁺) enhancers or multiple therapies for anti-inflammatory and immunomodulation also hold great promise. Considering a drug development strategy empowered by multi-disciplinary developments, nanomedicines with a broad spectrum of composition, morphology, surface chemistry, and surface modifications can precisely manipulate the microenvironment to effectively treat aging-related diseases. Therefore, the design principles and formulation strategies on engineered nanotechnology-based drug delivery system (NDDS) targeted SnCs are emphasized. We also systematically review the applications of aging-related therapies in specific diseases, including NDs, CVD, bone and joint diseases, cancer, fibrotic diseases, and chronic obstructive pulmonary disease (COPD) etc. Finally, a strength, weakness, opportunity and threat (SWOT) analysis is introduced from an economic perspective to comprehensively evaluate the future development directions of the therapeutic strategies targeting manipulating SnCs and treating aging related diseases.

2. Mechanisms of cellular senescence

2.1. Telomere shortening and replicative senescence

Telomere shortening occurs during DNA replication due to the intrinsic end-replication problem. In the absence of compensatory mechanisms, such as telomerase activity or telomere recombination, progressive telomeric attrition ensues with each cell division, which can result in critically short telomeres and replicative senescence [64,65]. Specifically, the RNA primers on the lagging strand cannot be completely replaced during DNA replication. As a result, small single-stranded gaps remain, which eventually form 3′ G-rich overhangs [66]. These overhangs are recognized as dysfunctional telomeres by the ATM/ATR kinase cascade, initiating a sustained DNA damage response (DDR) and triggering replicative senescence through markers such as γH2AX and 53BP1 [67]. In advanced telomere dysfunction, ATM/ATR kinases induce epigenetic derepression of the CDKN2A locus via sustained DDR signaling, driving the overexpression of p16INK4a. Elevated p16INK4a binds to CDK4/6, blocking cyclin D-dependent phosphorylation of Rb and maintaining its active hypophosphorylated state. This stabilizes Rb-E2F complexes, enforcing G1/S arrest [[68], [69]]. Meanwhile, oxidative stress also accelerates telomere shortening. Reactive oxygen species (ROS) induced by high glucose and hydrogen peroxide preferentially attack the guanine rich TTAGGG repeat sequences in telomeres, inhibiting telomerase activity and caused significant telomere loss in skin fibroblasts of diabetes patients [70].

2.2. DNA damage accumulation

DNA damage refers to abnormal changes in nucleotide sequence or double helix structure of DNA molecule [71]. DDR orchestrates context-dependent responses, such as transient cell cycle arrest, DNA repair, autophagy, apoptosis, or senescence. It is worth noting that DDR-mediated cell cycle arrest may be transient. However, in cases of severe DDR, the cell may enter a state of long-term cell cycle arrest [72,73]. Once telomeres shorten to the Hayflick limit, the 3’ G-rich overhangs become exposed. These overhangs represent a distinct form of DNA damage and are stabilized through TRF2-dependent T-loop formation [74]. When T-loops collapse, exposed telomeres mimic DSBs but trigger amplified DDR signaling via ATM kinase hyperactivation and telomere dysfunction-induced foci [75]. This unique damage context explains their exceptional senescence-inducing capacity, as persistent telomeric DDR drives irreversible p21-mediated cell cycle arrest and SASP secretion [67,76]. In summary, the generation of DNA damage and the activation of DDR are confirmed causes of cellular senescence. Further in-depth basic research is still needed to tentatively explore and expand the link between cellular senescence and DDR.

2.3. Epigenetic erosion

Senescence-driven heterochromatin erosion is frequently associated with abnormal expression of histone-modifying enzymes, including reduced expression of SUV39H1 and SETDB1 methyltransferases, along with elevated levels of demethylases KDM4A or KDM4B [77,78]. Similarly, heterochromatin protein 1 depletion accelerates heterochromatin decondensation and senescence, while its restoration stabilizes chromatin architecture and attenuates premature senescence [77,[79], [80], [81], [82]]. Furthermore, several non-classical factors that regulate heterochromatin status were reported to significantly affect cellular senescence, including circadian rhythm clock regulator [80,[82], [83], [84]], sirtuin family members [85,86], RNA N6-methyladenosine (m6A) modification regulators [[87], [88], [89]], and apolipoprotein E (APOE) [90]. Evidence also indicated that p21 activation dominates the initial phase of senescence establishment by mediating transient arrest, whereas p16 accumulation enforces long-term senescence maintenance [91]. Senescence-related epigenetic mechanisms provide crucial insights into the molecular drivers of cellular senescence and organismal decline, offering theoretical foundations for developing anti-aging interventions.

2.4. Mitochondrial dysfunction

Mitochondrial dysfunction acts as both the cause and consequence of cellular senescence [92]. It induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial kinetic disorders, and changes in mitochondrial autophagy (Fig. 3). The senescence regulator p53 suppresses mitophagy by binding Parkin and blocking its transport to dysfunctional mitochondria, thereby inhibiting degradation of dysfunctional mitochondria [93,94]. Crucially, p53-mediated mitophagy inhibition exacerbated cardiac dysfunction in aged models, a phenotype that was reversed by Parkin overexpression or p53 deletion [95]. Recent studies also showed that altered pH deteriorates autophagy function, thereby reducing autophagy-dependent substrate clearance [96]. However, the regulation of autophagy by pH changes is not universal, and its effect is highly dependent on cell type and specific pathophysiological background. Further elucidating the dynamic regulation of autophagy by monitoring the critical pH changes in the autophagic flux with tools like small-molecular fluorescent pH probes, will contribute to a deeper understanding of the fine regulatory mechanisms through which dysregulated autophagy elicit cellular senescence, particularly those triggered by mitochondrial dysfunction [97]. Furthermore, mitochondrial calcium overload caused by NAD⁺/NADH ratio imbalance and Ca²⁺ flux regulation disorders can also lead to mitochondrial dysfunction [92,98,99] Another study identified that mitochondrial double-stranded RNA release into the cytoplasm served as a key driver of senescence-associated inflammatory phenotype, which was elaborated in the next section [100]. Paired with mitochondrial dysfunction, metabolic pathways, particularly glucose and lipid metabolism, become dysregulated during senescence. These alterations disrupt cellular energy homeostasis and metabolite flux, thereby reinforcing senescence phenotype [[101], [102], [103]].

Fig. 3.

Mechanism of mitochondrial dysfunction. Mitochondrial dysfunction can trigger inflammation by activating damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Figure created with BioRender.com.

2.5. Senescence-associated secretory phenotype

Cellular senescence drives multiple phenotypic alterations with a potential mechanism involving the transcriptional activation of the SASP program (Fig. 4). SASP consists of cytokines, chemokines, growth factors, and ECM-degrading enzymes. These secreted factors can stabilize the senescent phenotype, reshape the surrounding tissue environment, and ultimately influence systemic physiology [104]. IL-1α and IL-1β, as prominent mediators of SASP, activate downstream interleukins (e.g., IL-6, IL-8) via autocrine/paracrine signaling, thereby reinforcing proliferation arrest [105,106], consolidating senescence programs [107] and mediating immune responses [106]. IL-6 and IL-8 executes oncogene-induced senescence through autocrine signals to reinforce tumor-suppressive arrest. Beyond autocrine actions, these cytokines orchestrate paracrine senescence across diverse pathological contexts, amplifying systemic senescence effects [105,107,108]. Transforming Growth Factor-β (TGF β) is a SASP factor that promotes aging and upregulates other SASPs in the microenvironment through paracrine pathways [109,110]. Small EVs, particularly exosomes (30–150 nm), were recently identified as critical mediators in the senescent secretome transmitting paracrine senescence effects through intercellular communication [111,112]. Furthermore, chronic inflammation accelerates immune cell senescence, leading to weakened immunity that fails to eliminate SnCs and inflammatory factors, thereby creating a vicious cycle of inflammation and aging [113].

Fig. 4.

Major regulators and pathways involved in SASP regulation. SASP factors can be regulated at transcriptional, translational modifications and epigenetic levels targeting SnCs. Figure created with BioRender.com.

2.6. Protein homeostasis imbalance

Numerous studies showed that protein synthesis capacity declines during senescence and aging [[114], [115], [116]]. Disruption of protein homeostasis is closely linked to cellular senescence and is also implicated in NDs such as Alzheimer's disease (AD) and Huntington's disease [[117], [118]]. The core mechanisms of protein homeostasis imbalance that drive cellular senescence mainly include translation errors and ribosome dysfunction, collapse of the protein folding system, and dysfunction of the degradation pathway, ultimately leading to organ decline and age-related diseases. Furthermore, protein degradation declines with age, affecting all proteasome, macroautophagy, and chaperone-mediated autophagy systems. During aging, SAGA-associated factor 29 (SGF29) facilitates the recruitment of MED4/RNA polymerase II transcription complexes and activates CDKN1A (p21). This activation disturbs protein homeostasis and promotes the transition to irreversible cellular senescence [119]. These findings suggest that maintaining proteostasis through enhanced protein degradation (e.g., using PROTAC technology or activating autophagy), improved folding capacity (through molecular chaperone activators like HSF1 inhibitors), and suppression of abnormal translation (such as NAD⁺ boosters) represents a core therapeutic strategy for combating age-related diseases.

3. Anti-cellular senescence-based drug discovery strategies

Numerous studies have shown that cellular senescence is closely related to the occurrence and development of various diseases [[120], [121], [122], [123], [124]]. Targeted clearance of SnCs, intervention in SASP and biological mechanisms, and even the subtle chemical changes in SnCs are considered effective strategies for treating age-related diseases. These therapies can be broadly categorized into senolytics and senomorphics. Additionally, replenishing depleted NAD⁺, gene and epigenetic regulation, as well as various anti-inflammatory and immunomodulation therapies, are also being discussed (Fig. 5 and Table 1).

Fig. 5.

Intervention strategies for combating cellular senescence. Figure created with BioRender.com.

Table 1.

Anti-aging drug treatment strategies, mechanisms and existing issues.

Strategies		Mechanisms	Representative drugs	Existing issues	Delivery system
Senolytics	Senescent cell anti-apoptotic pathway	Induce apoptosis and programmed cell death [3].	DQ combination [4], ABT-263 [5], A1331852 [6], A1155463 [6], fisetin [6], piperlongumine [6], baicalein [7]	Off-target effect, Incomplete absorption, High first-pass metabolism, Low bioavailability, Few options for local delivery	Small molecules, bioactive natural products and their derivatives or biological agents
Senomorphics	NF-κB pathway inhibitors	Change or reverse the state of ageing cells, or at least significantly reduce SASP secretion [8].	hESC-Exos [9],Metformin [10]	Weaken immune surveillance	Exosomes derived from human embryonic stem cells
	mTOR pathway inhibitors	Induce autophagy or inhibit protein synthesis [11].	Rapamycin [12]		Liposomes
	p38 MAPK pathway inhibitors	Delay oxidative stress-mediated aging or reduce the impact of H2O2 on aging markers [8]	BIRB796 [8]		Small molecule inhibitor
NAD+ boosters	N/A	Supplement NAD+ precursors and inhibit NAD+ denigrating enzymes [13]	NR and NMN [14]	NAD+ cannot penetrate cell membranes and therefore cannot be directly supplemented; the oral bioavailability of NAD+ precursors is low, and their conversion rate is also controversial; clinical evidence is weak.	NAD+
Genes regulation	Sirtuin pathway activators (SIRT1, SIRT4, and SIRT6et al.)	Restore cell microenvironment, promote spontaneous clearance of SnCs, or enhance anti-aging defense [15]	Resveratrol, Curcumin, NAD+ precursor [16], SRT1720 [17], SLF-178 [18]	By regulating these longevity genes, new targets for reversing ageing and repairing damaged tissues are gradually emerging. Anti-ageing drugs targeting these pathways are gradually being developed, with some already entering clinical trials.	Liposomes, Polymeric NPs, Micelles
	mTOR pathway inhibitors (MTOR)	Regulate cellular metabolism, autophagy, and inflammatory responses [19].	Rapamycin [12], Spermidine [20], RTB101 [21]		Liposomes, Polymeric NPs
	AMPK pathway inhibitors (PRKAA1, PRKAB1et al.)	Inhibit of AMPK-activated autophagy lead to the accumulation of damage within SnCs, ultimately trigger apoptosis or necrosis [22].	Metformin [23], AICAR [24], MK-8722 [25]		Liposomes, Polymeric NPs
	FOXO3/SIRT1 (FOXO3 and SIRT1) synergistic activator	Upregulate antioxidant genes and reduce ROS accumulation; inhibit SASP and clear damaged proteins and organelles from SnCs [26].	Resveratrol [27], FOXO4-DRI [28]		NMN/NR nano-encapsulation, Liposomes, Polymeric NPs
	Telomere activators	Maintain or extend telomere length [29].	TA-65 [29]		Natural compounds
	Mitochondrial DNA editors	Inhibit miMOMP can significantly reduce the levels of inflammatory markers, inhibit mtDNA release, and improve aging [30].	N/A		Mitochondria-targeted modification
Epigenetic reprogramming	N/A	Target TET enzyme [31]	dCas9-TET1 [31]	TET1 may nonspecifically demethylate non-target genes, and epigenetic characteristics vary greatly between different tissues or ageing types.	dCas9
	N/A	Repair a base mutation in the nuclear lamin protein A (Lamin A) [32].	Base editing [32]	Base editors are too large to distinguish between SnCs and normal cells; base editors may bind to non-target sequences, causing random mutations in the genome.	Adeno-associated virus
	N/A	Convert mature differentiated cells into pluripotent stem cells [33].	OSKM reprogramming [33]	OSKM may globally alter chromatin structure, increasing non-specific binding of base editors; different tissues respond differently to OSKM and editing.	LNP-mRNA
	N/A	Activate longevity gene pathways, triple resistance to aging, stress, and malignant transformation [34].	SRC [34]	SRC may affect normal cells, leading to off-target effects; some SRCs are poorly water-soluble and have a short half-life; different subpopulations of SnCs respond differently to SRC, which may lead to drug resistance.	Exosome
Inflammatory network	Anti-inflammatory drugs	Chronic inflammation accelerates the aging of immune cells and can also trigger excessive production of ROS, accelerate telomere shortening and inhibit DNA repair [35].	Anti-GPNMB-CAR-T [36], Bispecific antibodies [37], Nanovaccines [38], IL-1β inhibitors [39]	Systemic suppression of inflammation may weaken normal immune defences; senescent cell heterogeneity causes some subpopulations to escape clearance; sustained immune regulation may induce autoimmune reactions.	LNP-mRNA, Liposomes, Polymeric NPs
Others	N/A	Promote the cleavage and activation of prodrugs, and enable cytotoxic drugs loaded onto galactose polymer-coated NPs to be preferentially released into SnCs, thereby inducing apoptosis [40].	β-gal [41]	Lysosomal enzymes are widely present in all cells and lack specific recognition of SnCs. The lysosomal membrane of SnCs is prone to rupture, leading to enzyme leakage and inflammation. Overactivation may disrupt normal metabolism.	Polymeric NPs
	N/A	Decrease electron transport chain efficiency, increase ROS, exacerbate oxidative damage; lysosomal membranes of SnCs are prone to rupture, activate NLRP3 inflammasomes [42].	Cardiac glycosides [43]	The restoration of mitochondrial membrane potential is cell-specific, and intervention may affect healthy cells; lysosomal rupture may trigger inflammation, and enzyme activity may be difficult to restore.	Mitochondrial membrane potential, Lysosomal acidification

3.1. Senolytics

Senolytics are a class of compounds, including small molecules, bioactive natural products and their derivatives or biologics, that can eradicate SnCs directly by inducing cellular apoptosis and programmed cell death [1,[125], [126], [127]]. Their core mechanism involves targeting overexpressed anti-apoptotic pathways in SnCs, particularly SnCs anti-apoptotic pathways (SCAPs), while bypassing the survival mechanisms of healthy cells [128,129]. Consequently, various senescence inhibitors have been developed against SCAP networks. Representative senolytic agents include the Dasatinib and Quercetin (DQ) combination, fisetin, piperlongumine, baicalein, BCL-2 inhibitors such as navitoclax (ABT-263), A1331852, and A1155463, as well as FOXO4/p53 interaction inhibitors and histone deacetylases (HDAC) inhibitor etc. These agents have been studied in clinical or preclinical trails, and show great potential for eradicating SnCs. A prime example is the DQ combination, first identified in 2015, which significantly impacts the clearance of SnCs from mouse adipose tissue, extending healthy lifespan by 36 % [4]. Recently, two clinical trials are approved to use the DQ combination for treating idiopathic pulmonary fibrosis, showing promising results in improving patients’ physiology [3]. Moreover, Senolytics therapy also demonstrates promising therapeutic effects in treating diabetic nephropathy, AD, and COPD. For example, a Phase 1 clinical trial involving oral administration of DQ showed efficacy in reducing cerebral amyloid protein deposits and blood biomarkers in early-stage symptomatic AD patients, while maintaining good safety, feasibility, and tolerability [130]. While the exact mechanism is not fully understood, these senolytic agents exerts broad-spectrum anti-aging activities by disrupting several pro-survival networks, including Ephrin-dependent receptor signaling, PI3K/Akt, tyrosine kinase receptor (TKR), growth factor receptor (GFR), hepatoprotein receptor B1 (EFNB1), SRC kinase, HSP90, p53, caspase inhibitors and BCL-2 members [[131], [132], [133], [134], [135]].

However, due to the heterogeneity of SnCs, different senolytics may exhibit varied beneficial effects. For example, fisetin has no effect on radiation-induced bone loss, whereas the DQ combination does [136]. Notably, the main challenge limiting the clinical application of senolytic therapy lies in its off-target effect, which fails to effectively distinguish harmful SnCs from functionally dormant cells, inevitably causing damage to normal cells and triggering adverse reactions like non-specific cytotoxicity, thrombocytopenia (induced by navitoclax), pulmonary vascular toxicity [137,138]. Moreover, SnCs are not entirely harmful, they also play positive roles in wound healing, tissue repair and cancer treatment. In particular, SnCs can rapidly activate immune cells and hold great potential for tumor combat [139]. Complete elimination of these cells may therefore lead to side effects. Senolytic therapy also cannot address the persistent generation of SnCs, making it difficult to fundamentally reverse aging. Additionally, most senolytic drugs are administered systemically, with few options for local delivery and suffer from incomplete absorption, high first-pass metabolism, and low bioavailability. For these reasons, specific intervention of SnCs is emerging as a powerful means to counteract aging and aging related diseases. Gradually, senotherapy is developing into leverage additional aging features and enhance immune-mediated clearance, or further develop antibody-senolytic conjugate drugs based on surface markers of SnCs (such as uPAR, DPP4) to enhance the capability to target SnCs. A recent study revealed that a new senolytic agent, targeting the survival-dependent molecular pathway in SnCs, can effectively inhibit the activity of the capsid protein complex I (COPI), which resulted in the entrapment of the garbage SASP secretion, leading to a self-destruct mechanism similar to ingesting poison, thereby triggering the self-apoptosis of SnCs [140]. More importantly, exploring new combination therapies, such as senolytics combined with SASP inhibitors (like JAK inhibitors) or immunotherapies that enhance macrophage clearance of SnCs, would become a mainstream strategy to avoid the challenges associated with single senolytic drugs in clearing all types of SnCs.

3.2. Senomorphics

Unlike senolytics which directly eliminate SnCs, senomorphics refer to a class of treatments aimed at altering or reversing the state of SnCs, or at least significantly reducing their ability to secrete harmful substances like SASPs [141]. Senomorphics function by targeting and modulating key signaling pathways within SnCs, such as NF-κB, mTOR, cGAS-STING, JAK/STAT, ATM/ATR, and p38 MAPK, aiming to reduce the release of pro-inflammatory cytokines, chemokines, proteases, etc. [[142], [143], [144]]. Senomorphics also attempt to reverse certain senescence-associated functional impairments to restore cellular function, although fully reversing the senescent phenotype may be very challenging. Additionally, they regulate the abnormal metabolism in SnCs to improve metabolic status. Compare to senolytics, this strategy effectively regulates the activity of SnCs, providing a gentler and more controllable effect, thus theoretically avoiding acute side effects or tissue damage risks associated with massive cell death.

Excitingly, recent studies indicate that aging is not primarily driven by cells reaching their natural limits of proliferation, but rather by stressors such as oxidative stress and DNA damage [9]. By alleviating these stressors, SnCs can be rejuvenated to restore their proliferative capacity, bringing them closer to their inherent growth potential. For example, human embryonic stem cell-derived exosomes effectively reverse senescence phenotypes in both in vitro and in vivo by inhibiting key cell cycle arrest factors, thereby rejuvenating SnCs. This groundbreaking study introduces the innovative "senoreverse" strategy, which reverses cellular and organismal aging without altering the intrinsic properties of SnCs. Unlike traditional "senomorphics" therapies that may compromise immune surveillance by suppressing SASP secretion, "senoreverse" mitigates the risks of tissue damage and immunosuppression, addresses critical limitations of current anti-aging therapies, and provides a more gentle and sustainable intervention for SnCs. Mechanically, miR-302b is a crucial component for reversing senescence, targeting and reducing the expression of cell cycle inhibitors Cdkn1a and Ccng2, challenging the classical theory of the irreversible nature of cellular senescence. This study further demonstrates that miR-302b may indirectly enhance cellular function through epigenetic mechanisms such as DNA methylation and histone modification. miR-302b also effectively alleviates SASP secretion and chronic inflammation without raising safety concerns, which is consistent with the "senomorphics" strategy. To these ends, this groundbreaking approach may expand the theoretical framework and application scope of the "senomorphics" strategy, but also opens new avenues for the development and application of nucleic acid drugs, holding significant academic value and clinical promise.

3.3. NAD ⁺ boosters

NAD⁺ is a coenzyme for cellular energy metabolism and signal transduction, extensively involved in regulating energy production, DNA repair, epigenetic regulation, oxidative damage, and inflammatory response. Research indicates that NAD⁺ depletion within cells is typically associated with aging [145], and its decline is related to the progression of ageing-related diseases. Strategies include supplementing NAD⁺ precursors, such as nicotinamide riboside (NR) and β-nicotinamide mononucleotide (NMN), and employing small-molecule inhibitors to target NAD⁺ degrading enzymes. However, NAD⁺ precursors exhibits low oral bioavailability and poor cell membrane penetration, restricting its biomedical applications [13]. Besides, its dose-response relationship is not well-defined, potentially leading to hepatotoxicity [146]. Recently, a review of 25 clinical trials on NR supplements indicated minimal clinically relevant effects, though potential benefits in reducing inflammation and treating severe diseases were noted [147].

3.4. Genes and epigenetic regulation

Researchers have revealed several genes associated with extending lifespan, including the SIRT1, SIRT3-5, SIRT6, TERT/TERC, SOD2, PON1, and FOXO3 genes, etc [[148], [149], [150], [151], [152]]. By modulating these longevity genes, new targets are emerging to reverse aging and enhance the function of damaged tissues [153]. Emerging drugs like SLF-178 and FOXO4-DRI are awaiting the results from Phase III clinical trials [18]. These activators or inhibitors typically exert their anti-aging effects by regulating protein synthesis, activating autophagy, enhancing mitochondrial function, inhibiting immune pathways, or reducing inflammatory factors. Additionally, telomere activators such as TA-65 and mitochondrial DNA editors can also repair DNA damage, maintain telomeres, and optimize mitochondrial function [29].

To our knowledge, aging is driven by the gradual loss of youthful epigenetic information [154]. Latest researches suggest that aging is transitioning from an irreversible natural process to a treatable pathological state [9]. Unlike mutations or changes in DNA sequences, epigenetic modifications are reversible. Epigenetic reprogramming, which promotes DNA demethylation, chromatin remodeling, nuclear structure restoration, and mitochondrial activation, has the potential to regulate cell fate. For instance, base editing tools delivered by adeno-associated virus (AAV) repaired a base mutation in the nuclear lamin protein A (LAMIN A) of progeria mice, extending their lifespan from 215 days to 510 days [32]. Additionally, senescence-resistant human mesenchymal progenitor cells (SRC) have been successfully reprogrammed using synthetic biology strategies to activate longevity gene pathways, thereby conferring triple resistance to aging, stress, and malignant transformation [34]. These approaches provide a customizable cell therapy paradigm for aging interventions, expand the research dimensions of cell therapy, and support the development of next-generation intelligent cell anti-aging technologies.

3.5. Anti-inflammatory and immunomodulation

SASP promotes chronic inflammation and can induce normal cell senescence, which is commonly accompanied by persistent oxidative stress, chronic inflammation, and immune system and organ dysfunction [35]. Simultaneously, chronic inflammation accelerates immune cell aging, leading to weakened immune function and creating a vicious cycle referring to inflammation and aging. Chronic inflammation can also trigger the overproduction of ROS, accelerate telomere shortening, and inhibit DNA repair [155]. Persistent inflammation in organs such as the bone marrow, liver, and lungs can lead to organ damage and age-related diseases. Therefore, the inflammatory network is a potential target for anti-aging efforts. Studies have shown that inhibiting the pro-inflammatory protein IL-11 significantly improves the healthspan of aged mice [135]. Anti-inflammatory drugs originally approved for specific disease indications, such as metformin, aspirin, rapamycin, and ibuprofen, have been rejuvenated due to their anti-aging effects. Monoclonal antibodies targeting pro-aging inflammatory factors or their receptors, as well as novel anti-inflammatory drugs like anti-GPNMB-CAR-T, bispecific antibodies, nanovaccines, and IL-1β inhibitors designed to block cytokine signaling, are gradually being used to treat age-related diseases [[37], [156], [157]]. In the future, more research on anti-inflammatory drugs to treat age-related diseases is expected to emerge, potentially leading to new treatment approaches.

3.6. Other approaches

Other characteristics of SnCs also aid in their clearance. For example, the increased activity of lysosomal enzymes, such as SA-β-gal, in SnCs facilitates the cleavage and activation of prodrugs. This enables the preferential release of cytotoxic drugs into SnCs after loading into galactose polymer-coated nanoparticles (NPs), thereby inducing apoptosis [[40], [158], [159]]. A lysosomal metabolic targeting molecule prodrug was synthesized to achieve both high specificity and broad-spectrum elimination for SnCs. By targeting lysosomes with enhanced membrane sensitivity, using a linker cleavable by activated lysosomal enzymes, and efficiently identifying the elevated lysosomal content in SnCs, this tailor-made prodrug enabled spatially restricted senescence intervention, significantly expanding the applicability of senotherapy across various diseases [160]. However, this strategy may also result in off-target effects, as activated macrophages and other non-SnCs also express high levels of SA-β-gal. Additionally, even minor chemical changes, such as alterations in mitochondrial membrane potential and lysosomal acidification within SnCs, can be exploited for the preferential removal of SnCs, as demonstrated in studies on CVD selectively clearing SnCs [161].

4. Engineered NDDS targeted anti-aging therapy

Currently, a variety of anti-aging agents and strategies are put forward, as previously discussed. However, most anti-aging agents, including rapamycin, resveratrol, and senolytics, show low water solubility and poor pharmacokinetics [[162], [163], [164]]. Traditional methods result in systemic drug distribution, with only a small amount reaching specific organs or SnCs, exacerbating severe side effects. Furthermore, immune suppression, off-target effects, neurodegeneration, short half-lives or functional retention times may pose patient compliance and treatment accessibility [165,166]. These factors collectively represent the technical challenges that restrict the use of stem cell therapy in anti-aging treatments [167].

With the development of multi-disciplinary drug development strategies, NDDS possessing adjustable composition, size, shape, surface chemistry, and texture properties, enable them to not only provide therapeutic effects, but also facilitate the transport of drugs across multiple physiological barriers for controlled drug release [168]. Crucially, NDDS enables precise targeted delivery, controlled drug release, and multifunctional synergistic therapy, opening up new avenues for the development of anti-aging drugs and expending clinical application. Next, we will concentrate on the design of NDDS and anti-aging targeted drug therapy based on the profound biological mechanisms of cellular senescence.

4.1. Combination therapies

SnCs vary across different tissues and can effectively vade immune system surveillance, posing major challenges for precise identification and targeted therapy. Combination therapies hold great promise in treating age-related disease by intervening in multiple pathological processes simultaneously [169]. For instance, Gkioni et al. indicated that compared to the use of trametinib alone (which extends mouse lifespan by 5 %–10 %) [170] and rapamycin alone (which extends lifespan by 15 %–20 %) [170,171], the combined treatment with rapamycin and trametinib increased lifespan by 30 % [172]. Furthermore, the synergistic effect is not merely a result of dose addition, but is due to the unique gene activity changes triggered by the drug combination [173]. For example, the combination of dendrobium officinale polysaccharides and spermidine exhibited synergistic anti-aging effects. At concentrations of 250 mg/L for dendrobium officinale polysaccharides and 29 mg/L for spermidine, the lifespan extension benefits were maximized, which may primarily be mediated through alterations in lipid metabolism pathways [174]. In another case, a cocktail of rapamycin, acarbose, and phenylbutyrate, targeting mTOR1 signaling, insulin signaling, histone deacetylase binding, and other pathways related to DNA damage, inflammation, senescence, and autophagy, prevented age-related cognitive decline in mice [175]. Additionally, a binary tetrahedral DNA NDDS was innovatively developed that leverages anti-inflammatory and antioxidant properties of tetrahedral DNA, while encapsulating small interfering RNA (siRNA) targeting Raptor, thereby slowing cellular senescence and enhancing anti-aging therapy synergistically [165]. A recent study also reported that combining regenerative medicine with senotherapies targeting SnCs could alleviate inflammation and slow down cellular aging processes, potentially offering a revolutionary breakthrough in the treatment of diabetic nephropathy [166].

4.2. Drug loading

Numerous therapeutic agents that target cellular senescence and possess dimensions with spacious internal cavities and branched architectures, along with dense functional groups, can be classified as nano-polymers or nanomedicines. Through scientific design focusing on the surface chemistry and texture characteristics of nanomedicines, as well as modification with functional groups, sensitive moieties, and specific ligands, researchers have fully harnessed their potential as promising drug delivery systems with multifunctions, such as controlled release, precise targeting, senescence microenvironment reprogramming, improved drug stability, and enhanced biosafety. In this context, the encapsulation of therapeutic agents is the first and critical step to achieve efficient drug delivery and disease treatment.

From a structural perspective, internal and external drug loading are two main strategies for efficient drug loading in NDDS. More importantly, they enable the combined application of multiple therapeutic agents for aging-related diseases. To be specific, external drug loading involves attaching drugs to the surfaces of NDDS through electrostatic adsorption, non-covalent bonding, or covalent. Electrostatic adsorption for drug loading is simple and efficient, but may lack stability and easily dissociate under physiological conditions. Non-covalent binding uses weak interactions, such as hydrogen bonds and van der Waals forces, to attach drugs to the NDDS, offering high flexibility. Covalent binding provides high stability and sustained drug release. Molecules can chemically bond to functional groups on the surface of NDDS, thereby modulating the drug's physical state and solubility as well as enabling controlled drug loading and release. In contrast, internal drug loading primarily relies on the branched, porous, and cavity structures of NDDS, with drugs being directly embedded or efficiently encapsulated through hydrophobic interactions or hydrogen bonds. For example, the canonical senolytics DQ were encapsulated in mesoporous polydopamine through π-π stacking and hydrogen bond adsorption, followed by coating with a galactan-modified layer to develop a multifunctional nanoplatform similar to double locks [176]. Once these nanosenolytics were subsequently engulfed by the lysosomes of SnCs, DQ released in response to higher levels of SA-β-gal and lower pH values, thereby specifically and efficiently eradicating SnCs with minimal impact on normal cells [176]. Eduardo et al. also proposed a potent combination of senolytics and NAD⁺ boosting, which enhanced the synergistic benefits in aging, healthy lifespan, and longevity [177]. Given the co-loading capacity of NDDS, exploring new combination therapies, such as senolytics + SASP inhibitors (like JAK inhibitors), mitochondrial-targeted drugs (such as SS-31) + NMN, or immunotherapies that enhance macrophage clearance of SnCs, will become possible to avoid the difficulties encountered by single senolytic drugs in clearing all types of SnCs. Despite the extensive applications of these two drug-loading strategies in pharmaceutical development, the selection of drug-loading methods in practical implementation requires comprehensive consideration of multiple factors, including drug properties (such as molecular weight, solubility, and stability), therapeutic objectives, and carrier characteristics.

4.3. Delivery routes and bio-distribution

Aging-related diseases involve complex organs, barriers and pathophysiological states. By specifying the size, shape, structure, surface chemistry, and delivery routes of NDDS, they will be capable of overcome various physiological barriers and achieve targeted delivery to different organs, exhibiting optimal absorption, targeting, and clearance characteristics. We then focus on understanding the in vivo transport process of NDDS and provide guidance for precise treating of various aging-related diseases.

The delivery routes, including oral delivery, intravenous, subcutaneous or intramuscular injection, inhalation administration, and topical application, determine the absorption and biological fate of various therapeutic agents. Oral administration offers the highest safety and compliance, providing systemic therapeutic effects after absorption through the small intestine. However, oral administration often faces complex gastrointestinal barriers, including the acidic stomach environment, microorganisms and enzymes, and the thick mucus layer and epithelial cell layer. Currently, most senolytic drugs are administered systemically, with few options for local delivery and suffer from incomplete absorption, high first-pass metabolism, and low bioavailability. For example, the oral bioavailability of NMN preparations is less than 10 %. When NMN is taken sublingually, it is absorbed directly through the oral mucosa, increasing the bioavailability to 12 %–15 %. Liposome-encapsulated NMN further increases the oral bioavailability to 20 %–25 %. Nasal delivery, as a non-invasive method, offers advantages as safety, efficacy, and targeting. In AD therapy, nasal drops containing stem cell exosomes precisely and efficiently reached brain lesion areas, providing a new targeted therapeutic paradigm for NDs [178].Intravenous administration can directly deliver drugs into the circulatory system, offering rapid therapeutic effects, improving overall metabolism, enhancing immunity, and repairing the function of multiple organs. Especially, topical therapy can directly target the lesion area, improve precision and reduce systemic side effects associated with oral or injectable treatments. For instance, osteoarthritis (OA) treatment often involves intra-articular injection. Exosomes secreted by stem cells from human exfoliated deciduous teeth (SHED-Exos) can delay tendon degeneration when administered systemically. When applied locally, SHED-Exos reduced the formation of SnCs in ectopic bone, thereby restoring the endogenous tendon regeneration and repair capabilities of aged rats in both function and structure [179]. The combination of dermal layer injections of mesenchymal stem/stromal cell (MSCs) with hyaluronic acid enhances skin elasticity, with effects lasting 1–2 years [180]. Clinical trials have demonstrated that MSCs can cross the blood-brain barrier and improve cognitive function in Alzheimer's disease patients [181]. In addition, inhalation is one of the most effective methods for treating lung disease. For example, Chang and colleagues reported that aerosol inhalation of exosomes derived from human umbilical cord MSCs significantly improved bleomycin-induced pulmonary fibrosis in mice, offering hope to patients with interstitial lung disease, COPD-related pulmonary fibrosis, and other conditions [182]. In summary, various delivery routes significantly impact bioavailability and distribution. Although oral administration is convenient, it may result in incomplete absorption due to gastrointestinal conditions and first-pass metabolism. Intravenous injection, while rapid in delivering medication to the bloodstream, carries risks of tissue trauma and infection. Therefore, anti-aging therapies necessitate a careful evaluation of drug properties, patient conditions, and treatment goals to optimize delivery methods, maximizing efficacy while minimizing adverse effects.

4.4. Targeted therapy and precision medicine

NDDS can be designed to differentiate SnCs from normal cells, thereby significantly enhancing the intracellular accumulation and controlled release of senolytic drugs in aged tissues compared to healthy ones. In practice, passive, active, homologous, and receptor-ligand mediated targeting can be combined to design multifunctional NDDS that balance targeting ability, therapeutic effect, and toxicity (Fig. 6). The passive targeting is enhanced by the enhanced permeability and retention (EPR) effect, which results from changes in blood vessels and blood flow at inflammatory sites. For example, ultra-small nanoliposomes with particle sizes less than 40 nm significantly enhanced skin penetration and retention performance, where the unsaturated lecithin components provided excellent performance in clearing ROS [183]. Additionally, nanoliposomes can efficiently transport multiple anti-aging agents, such as coenzyme Q10, while preserving their physical stability. The local application of these nanoliposomes significantly suppressed UVB-induced MMP-1 production and enhance type I collagen synthesis in skin cells, effectively repairing photo-aged skin [184]. More importantly, cellular senescence biomarkers, including overexpressed integrin αvβ3, uPAR, DDR1, CXCR2, SCARF1 receptors, lipofuscin, SA-β-gal, etc., can be utilized to tailor and develop SnCs-specific nanotherapies. For instance, Vassilis et al. [185] utilized the accumulation of lipofuscin in SnCs to develop an efficient senolytic platform, which consisted a lipofuscin-binding domain scaffold that bound dasatinib through ester bonds as a senolytic agent to construct GL392. The compound was subsequently encapsulated in micelles for selective clearance of SnCs in vitro and in vivo through targeted release of senolytic drugs, thereby reducing toxic side effects. Tang et al., [186] designed a bionic NP coated with retinal pigment epithelium (RPE) cell membranes loaded with resveratrol, where the RPE membrane provided homologous targeting and simultaneously reduced systemic exposure. Furthermore, mesenchymal stem cell exosomes, which were lipid vesicles approximately 100 nm in diameter, function as cellular couriers. They carried biological molecules, including proteins and RNA, and precisely regulated cell function, serving as a nano-rescue for aging-related diseases [187]. The increased lysosomal SA-β-gal level was recognized as a hallmark of cellular senescence, which was widely used to identify SnCs and to specifically target them for elimination, essentially by utilizing a galactose-modified surface layer [188]. Tan et al. designed a specialized nanotuner that transformed senescent tumor cells from adversaries into allies in the remodeling of the tumor microenvironment (TME). Specifically, this nanotuner targeted metabolic abnormalities and initiated cascading artificial reactions through chemiluminescence resonance energy transfer mechanisms, which trigger self-initiated and self-sustaining photodynamic processes for enhanced singlet oxygen production, converting cellular senescence into pyroptosis [189]. An energy metabolism-engaged NDDS (EM-eNMs) was developed nanomedicine based on ultra-small black phosphorus quantum dots and selectively oxidized their surface using contact-electro-catalysis, which can inhibit excessive ATP production by specifically binding to ATP5B [190]. As structural analogs of inorganic polyphosphates (polyP), the internalized EM-eNMs were recognized by bone marrow MSCs (BMMSCs) as essential substances involved in energy metabolism, preferentially enriched in mitochondria to regulate mitochondrial morphology and function, thereby restoring the stemness and osteogenic potential of aged BMMSCs. In an aging mouse model, EM-eNMs can significantly reverse osteoporosis-induced bone loss by enhancing mitochondrial fission and autophagy, restoring the stemness and osteogenic potential of aged BMMSCs. Based on the discovering multiple biological characteristics and mechanisms of SnCs, as well as exploiting the ever-increasing SnCs-specific targets, senolytic agents can be specifically targeted and more efficiently delivered to aged cells or tissues, thereby restoring tissue homeostasis and rejuvenating the organisms.

Fig. 6.

Stimuli-responsive drug release and targeted anti-aging strategies of engineered nanomedicines. Figure created with BioRender.com.

4.5. Stimuli-responsive drug release

Stimuli-responsive NDDS, activated by internal or external stimuli, have garnered increasing attention to enhance therapeutic outcomes and reduce side effects. Specifically, engineered NDDS responsive to pH, ROS, and/or enzymes have been ingeniously designed for the treatment of age-related diseases (Fig. 7). Typically, the responsive mechanisms mainly involve the cleavage of chemical bonds, the degradation of materials, the erosion of surface coatings, and the breaking or activation of gatekeepers or switches, which are effectively facilitate controlled release via diffusion or erosion. Currently, researchers have developed a series of nanomedicines that can be cleaved by β-gal [40,[191], [192], [193]]. By this, the responsive moieties act as the protective locks in normal cells to prevent the side effects of the senolytic drugs, while β-gal in SnCs functions as a specific key to release the effector molecules, enabling targeted drug delivery and treatment. Furthermore, by leveraging the synergistic effects of three specific characteristics of SnCs (integrin αvβ3, high ROS levels, and compromised mitochondrial membrane integrity), Ryu et al. designed and developed a supramolecular nanosenolytics that self-assembly in SnCs utilizing ROS-responsive phenolic units, mitochondrial-targeting KLAK units, and senescence cell-targeting RGD peptides [194]. Ultimately, it interacted with the mitochondrial membrane in multiple ways, leading to mitochondrial damage and subsequently activating apoptosis. In other words, due to the specific accumulation of monomers and high levels of ROS, the oligomerization-induced self-assembly system selectively generates nanostructures in SnCs, not in normal healthy cells, aiding in the targeted removal of SnCs. Kong et al. [195] developed a smart framework nucleic acid by modified tetrahedral DNA NDDS (TDNs) with triphenylphosphine and single-stranded DNA sequences, which can self-assemble in situ in respond to specific nucleic acid biomarkers (e.g., microRNAs) presented in target cell. Moreover, TDNs networks precisely targeted and enveloped of mitochondria, causing their fragmentation and dysfunction, thereby enhancing cancer therapy efficacy. More importantly, TDNs targeting the senescence-associated microRNA (miR-34a) specifically eliminated SnCs in both cell and Caenorhabditis elegans models, significantly improving overall cell viability within mixed cell populations.

Fig. 7.

Delivery routes, therapeutic targets, and combining strategies for neurodegenerative diseases, cardiovascular diseases, arthritis, fibrosis disease, cancer, and other aging-related diseases. Figure created with BioRender.com.

5. Therapeutic strategies targeting aging-related diseases

5.1. NDs

NDs such as AD and dementia remain critical clinical concerns for elderly population [196,197]. Over 95 % of AD cases can be attributed to aging, where disease progression is often accompanied by cellular senescence-related abnormalities [198]. Established aging models, including INK-ATTAC (activated by AP20187) [199], p16-3MR (triggered by ganciclovir) [200], and p21-Cre transgenic mice [201] elucidated the role of SnCs in various diseases. Studies demonstrated that transplanting radiation-induced SnCs into young mice significantly compromised their physical function [202]. Conversely, eliminating p16-positive SnCs extended murine lifespan while delayed aging process in kidneys, heart, and adipose tissue [199]. Human translational studies further confirmed SnCs accumulation drove multi-organ pathological changes, particularly impacting cardiovascular, neurological, pulmonary, and musculoskeletal systems [203]. Thus, targeted interventions on SnCs may be beneficial for neurodegenerative diseases.

Current research identified numerous cell senescence-related targets for neurodegenerative disease treatment, including SA-β-gal [204], Nrf2 [205], JAK1/2 [[206], [207]], IKK/NF-κB [208], p38 MAPK [209], BCL-2 [207], BCL-XL [210], BCL-W [210], HSP90 [211], AKT [212], and ATM [213]. Specifically, SA-β-gal is widely recognized as a biomarker of aging, which is capable of identifying various SnCs. Senescence-specific killing compound 1 (SSK1) achieved selective clearance of SnCs by targeting SA-β-gal. However, due to the insufficient penetration through the BBB, SSK1 failed in AD treatment. Yin et al. [204] engineered a neurotransmitter-derived nanoplatform (SSK1-NPs) that enabled efficient delivery of SSK1 into brain parenchyma through endogenous lipid transporters, thereby overcoming the BBB. Upon cellular internalization, SSK1 was specifically hydrolyzed by lysosomal SA-β-gal, releasing the cytotoxic agent gemcitabine. This process selectively induced apoptosis in SnCs, thereby reducing amyloid-beta (Aβ) plaque deposition and significantly improving cognitive function in aged AD mouse. Alternately, unmodified PAMAM dendrimers were shown to traverse the inflamed BBB and accumulated within the intracranial inflammatory microenvironment in rabbit models. Liu et al. [214] reported a dendrimer-based NDDS capable of targeting the AD microenvironment. To overcome the drawbacks of single-target therapies, it also introduced three innovative components: Aβ mimetic peptide (KLVFFAED) targeting endocytic receptors, a polyethylene glycol (PEG)-based phenylboronic dendrimer with ROS responsive clearance capability, and the therapeutic peptide p-Nrf2 for maintaining oxidative stress homeostasis. By scavenging ROS and releasing p-Nrf2, the system synergistically restores cellular antioxidant capacity, effectively alleviating glial cell activation. Multi-target intervention can reduce the risk of drug resistance by balancing multiple pathological factors and minimizing adverse effects caused by excessive activation or inhibition of a single target. However, it may also pose challenges, such as uncontrollable in vivo processes and safety hazards associated with long-term use. Curcumin and its analogs (EF24) showed great potential in AD and depression treatment by eliminating SnCs through multiple targets including Bcl-2, Bcl XL, p38MAPK, and Mcl-1 [215]. NDDS, including polymeric NPs, micelles, liposome, cyclodextrin complexes, bioconjugates, lipidic NPs, nanoemulsions, and solid dispersions, were extensively explored to enhance the bioavailability of curcumin in brain-targeted delivery [216]. For example, chitosan-bovine serum albumin NPs were engineered to enhance drug delivery across the BBB. Applying curcumin, a potent anti-inflammatory agent, these NPs significantly targeted improved phagocytic clearance of Aβ peptide. Furthermore, these NPs exhibited suppression of the TLR4-MAPK/NF-κB signaling pathway, leading to reduced M1 macrophage polarization [[217], [218], [219]].

5.2. CVD

CVD encompasses a spectrum of congenital or acquired disorders affecting the heart and blood vessels, including ischemic heart disease, primary and secondary cardiomyopathies, heart failure, cardiac arrhythmias, and cerebrovascular disease (including stroke) [220]. With deepening understanding on CVD mechanisms and biological signaling complexity, SnCs have emerged as a recognized driver of aging and age-related CVD. The SnCs suicide transgenic (INK-ATTAC) mouse can trigger apoptosis of p16Ink4a-positive cells after treatment with an FKBP cross-linking ligand, AP20187 ¹⁶⁹. Lifelong removal of p16Ink4a-positive stem cells through INK-ATTAC profoundly attenuated CVD progression [199]. These findings propelled the application of senescence cell clearance strategies in CVD treatment. Recent studies revealed that clinically approved cardiac glycosides (e.g., digoxin and digitalis) may exert anti-aging effects by eliminating SnCs [221,222]. This discovery sparked concerns about the true mechanism for of action for such compounds, specifically whether therapeutic efficacy was achieved through the clearance of SnCs.

Sirolimus-eluting stents represent a standard intervention in coronary artery stenting for coronary artery disease, aimed at inhibiting vascular smooth muscle cell proliferation, attenuating immune cell infiltration, and reducing vessel restenosis [223]. A senolytic-eluting stent could provide systemic navitoclax's antiatherogenic effects while minimizing off-target toxicity. Alternatively, direct application of a senolytic-loaded patch to the epicardial surface may enable localized clearance of SnCs following myocardial infarction. However, given the poor applicability of local administration and the risk of high toxicity of systemic administration, alternative strategies were explored to optimize therapeutic outcomes. One promising approach involves the development of targeted NDDS that can specifically release senolytics at sites of cardiovascular injury. These NDDS can be engineered to respond to specific stimuli within diseased tissues, thereby ensuring local and controlled drug release. Additionally, the use of biomaterials that mimic the extracellular matrix of the heart can provide a supportive environment for cell regeneration and repair, further enhancing the therapeutic potential of senolytics in cardiovascular diseases. Kim et al. designed rosuvastatin (RSV) calcium encapsulated hyaluronic acid coated mesoporous silica (CD9-HMSN@RSV) functionalized with CD9-targeting antibodies, that can target clearance of senescent foamy macrophages and vascular endothelial cells in CVD [224]. In this study, CD9 activation triggered cellular senescence and accelerated atherosclerotic plaque progression. The hyaluronic acid (HA)-based capping shell can be degraded by plaque-derived hyaluronidase (HAase), accompanying with extracellular liberation of CD9 monoclonal antibodies (mAbs) during HA dissociation. Following intravenous administration, CD9-HMSN@RSV not only specifically targeted atherosclerotic plaques, but also effectively suppressed cellular senescence in atherosclerosis processes. However, special attention should be paid to the properties of the inorganic carrier itself, as silver and zinc oxide have been reported to induce upregulated secretion of SASP, which in turn induces aging [225]. Gao et al. [226] constructed a nanocapsule systems based on Pd/hCeO₂ loaded with the fatty acid-binding protein 4 (PBCP). Through cyclic tail vein administration, PBCP demonstrated enhanced targeting of vascular endothelial cells (ECs) by activating the HIF-1α/VEGF signaling pathway and regulating glycolipid metabolism, thereby protecting aged ECs. Moreover, this PBCP nanocapsule prolonged the lifespan and consistently improved abnormal phenotypes in aged mice by inhibiting immune inflammatory responses and SASP secretion, ultimately improving age-related vascular dysfunction.

5.3. Bone and joint diseases

OA is a chronic, multifactorial degenerative joint disorder characterized by progressive cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovial inflammation, culminating in joint pain and dyfunction. A dynamic interplay between mechanical stress, cellular dysregulation, and soluble mediators underpins OA pathogenesis. The OA joint microenvironment exhibits elevated inflammatory cytokines and oxidative stress, which promotes immune cell infiltration and polarize resident cells toward pro-inflammatory states. Critically, SnCs acquire a SASP, serving as a key source of pathogenic mediators that exacerbate OA progression [227]. Increased evidence suggests that senescent synoviocytes constitute a pivotal pathogenic factor in OA progression, emerging as a prominent research focus. Zhang et al. [228] identified elevated p16 expression in the OA synovium, indicating accelerated cellular aging in this tissue. A work by Jeon et al. [229] documented increased proportions of p16-and SA-β-gal-positive cells within OA synovial samples, further confirmed the activation of synovial senescence. Notably, Chen et al. [230]. demonstrated that targeted clearance of senescent synoviocytes effectively ameliorated OA pathogenesis, establishing senescence ablation as a viable disease-modifying strategy. Collectively, these findings confirmed that targeted intervention of senescent synoviocytes as a promising approach to the OA treatment.

IL-6 is an important SASP factor that drives cartilage degradation through the IL-6R/JAK2 pathways and also affects cartilage repair mechanisms. Zhao et al. [231] demonstrated that JAK inhibitors induced apoptosis and targeted clearance of p21 positive SnCs, proposing a new therapeutic target for OA. Ren et al. [232] constructed a ceria-based NPs that can mimic the biological activity of superoxide dismutase and catalase, thereby abating the noxious intracellular ROS and alleviating synovial senescence and SASP. ADAM19, a member of the ADAM (a disintegrin and metalloproteinase) endopeptidase family, was identified as a novel therapeutic target for rejuvenating senescent chondrocytes. Significant upregulation of ADAM19 expression was observed in senescent chondrocytes derived from both murine and human osteoarthritic joints, as well as in vitro cellular senescence models. The genetic knockout of ADAM19 not only markedly reduced SASP in chondrocytes, but also enhanced cellular proliferation and extracellular matrix component synthesis [233]. To therapeutically exploit this target, Wang et al. [233] developed a senescence-targeted delivery platform for the in vivo administration of siRNA, which can specific release of ADAM19-targeted siRNA within SnCs, achieving potent gene silencing efficiency. Furthermore, to reduce the repeated intra-articular injections and increase the specific clearance of senescent fibroblast like synoviocytes (FLSs), Chen et al. [234] systematically screened CX3 aptamers and constructed a CX3 modified liposome (CX3-LS) encapsulating with DQ, which achieved precise targeting of FLSs to facilitate DQ delivery into synovial tissue, and effectively inhibited the cartilage degradation in OA models. Feng et al. [235] engineered multifunctional esenchymal stem cell-derived small extracellular vesicles (MSC sEVs) modified with the cartilage-targeting peptide WYRGRL-PEG2K-DSPE (WPD) and loaded with siRNA targeting mouse double minute 2 homologue (siMDM2), aiming to target and remove senescent chondrocytes and restore cartilage metabolic balance. Results demonstrated that the multifunctional engineering strategy significantly enhanced MSC sEV uptake by chondrocytes, improved vesicle penetration through cartilage and prolonged their retention within the joint, thereby exhibiting remarkable efficacy in eliminating senescent chondrocytes and preserving cartilage matrix homeostasis. Besides, the cerium-based nanosystem (CeMOF/α-KG) possessed dual functions of antioxidation (scavenging ROS) and metabolic regulation (providing α-ketoglutarate). By activating the SIRT1-PGC-1α axis, it promoted mitochondrial biogenesis, resulting in a significant increase in the bone volume fraction (BV/TV) in osteoporotic models [189]. A recent review underscores the critical role of SnCs and SASP as promising targets for treating age-related bone diseases [136]. However, due to the heterogeneity of SnCs, different senolytics may exhibit varied beneficial effects, highlighting the importance of investigating tissue- and cell-specific effects of senolytic agents to promote the clinical translation of interventions aimed at eliminating SnCs and SASP.

5.4. Cancer

Numerous studies demonstrated that inducing genotoxic stress, hyperactivated mitogenic signaling, or oxidative stress can drive malignant cells into senescence, ultimately leading to stable cell cycle arrest and activation of the SASPs [[236], [237], [238]]. SASP produced by these senescent cancer cells can further inhibit proliferation in adjacent malignant cells, drug penetration through angiogenesis, and recruit tumor-suppressing immune cells [108,239]. However, the sustained presence of cellular senescence may be detrimental over time by fostering a pro-inflammatory and immunosuppressive TME [240]. Both preclinical and clinical evidence indicated that prolonged chemotherapy can induce chemoresistance through senescence-mediated mechanisms in cancer therapy [241]. Therefore, the combination of anti-tumor and anti-senescence therapies could theoretically inhibit tumor progression.

Recently, a docetaxel-tannic acid self-assembly (DSA)-based NPs was developed to provide potent anticancer and anti-ageing effects in prostate cancer cells and xenograft models through simultaneous inhibiting the TGFβR1/FOXO1/p21 senescence pathway and inducting apoptosis [241]. Shao et al. developed an oral nanocrystal co-assembly (Ali-Rux NPs) containing active ingredients, including alisertib (Ali) and ruxolitinib (Rux) [242]. Upon oral delivery, Ali-Rux NPs accumulated in TME, significantly inducing tumor cell senescence and reprogramming SASP secretion. Compared to immunogenic cell death or non-senescent counterparts, immunization with Ali-Rux orchestrated SnCs, significantly enhanced antigen-presenting cell activation and maturation, thereby amplifying anti-tumor immune surveillance [242]. β2 microglobulin (B2M), a member of the cell membrane surface protein family, is known to be overexpressed in SnCs. Studies demonstrated that B2M-based molecularly imprinted NPs (nanoMIPs) can precisely eliminate SnCs after a single-dose administration without causing cytotoxicity or systemic toxicity in mice [243]. Notably, when loaded with senolytic drug, this B2M nanoMIPs showed specific efficacy in eliminating senescent bladder cancer cells. Researchers isolated a 10-amino acid peptide (4N1Ks) from thrombospondin-1 (TSP1), which can form stable complexes with CD47 to antagonize downstream signaling cascades [244]. Leveraging this discovery, a biodegradable and biocompatible NDDS was developed, comprising vitamin E-sphingomyelin cores functionalized with 4N1Ks-conjugated PEG chains, in which CD47 enabled the surface-exposed 4N1Ks peptide to accurately guide NDDS delivery to SCs [244].

5.5. Fibrotic diseases

Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by irreversible alveolar destruction and interstitial scar formation. These structural alterations progressively compromise respiratory function and may culminate in eventual mortality [245]. Current anti-fibrotic agents, such as pirfenidone [246] and nintedanib [247], demonstrate efficacy in fibroblast targeting and collagen synthesis suppression, but fail in reversing established fibrotic lesions, facilitating pulmonary regeneration, or improving overall survival rates. The abnormal accumulation of SnCs (such as senescent alveolar epithelial cells and fibroblasts) and the dysregulated secretion of SASP factor can further exacerbate PF progression. The NAD consuming enzyme cluster of differentiation 38 (CD38) serves as a biomarker for cellular senescence that was elevated in type 2 alveolar epithelial cells (AEC2s) within the PF patients, representing CD38 as a potential therapeutic target. Long et al. [248] engineered a CD38 antigen receptor membrane-modified mesenchymal stem cell-derived extracellular vesicles (CD38-ARM-MSC-EVs), which selectively targeted senescent AEC2s in vitro and in naturally aged mouse models following intraperitoneal administration compared to MSC-EVs. Additionally, CD38-ARM-MSC-EVs effectively replenished intracellular NAD ⁺ pools in senescent A549 cells in vitro, reversed epithelial–mesenchymal transition phenotypes, and promoted cellular rejuvenation. Consequently, these vesicles mitigated multiple age-related cellular characteristics and alleviated PF pathology in aged mice. Besides, targeted delivery of senolytic drugs into senescent myofibroblasts can also alleviate PF. Shen et al. [38] discovered that the apoptotic resistance in senescent myofibroblasts driven by concurrent upregulation of the proapoptotic regulator BAX alongside anti-apoptotic factors BCL-2 and BCL-XL. Mechanistically, suppressing caspase activity with the inhibitor QVD-OPH or diminishing BAX expression significantly ameliorated DNA damage accumulation, thereby retarding the senescence process by intervening in minority mitochondrial outer membrane permeabilization. Importantly, the BAX activator BTSA1 specifically induced apoptosis in senescent myofibroblasts by amplifying minority MOMP into full permeability, while preserving non-SnCs with lower baseline BAX levels.

Liver fibrosis leads to progressive sexual organ dysfunction and ultimately organ failure, but the current treatment status is not optimistic. Inducing cellular senescence in activated hepatic stellate cells (HSCs) is recognized as a promising therapeutic approach for retarding the progression of liver fibrosis [249]. However, the persistent presence of SnCs may trigger a chronic, low-grade pro-fibrotic inflammatory- and immune dysregulation, thereby amplifying SnCs accumulation through a self-reinforcing feedback loop. Pharmacological activation of the cGAS-STING pathway represents a potential therapeutic strategy to induce senescence in activated HSCs [250]. However, targeted delivery of cGAS-STING agonists to activated HSCs faces significant challenges due to their anatomically inaccessible location, capillarization of liver sinusoidal endothelial cells (LSECs), and impaired transcellular substance exchange. Gu et al. developed an innovative anti-fibrotic approach that combined pro-senescence induction with enhanced immune clearance [251]. This strategy utilized albumin-mediated transcytosis to precisely deliver the potent cGAS-STING activator manganese to activated HSCs, subsequently triggering HSCs senescence, and finally achieving significant antifibrotic efficacy in vivo while exhibiting negligible systemic toxicity [251].

5.6. Others

COPD have also been reported to be associated with increased SnCs. In COPD patients, endothelial and epithelial cells exhibit heightened DNA damage [252] alongside multiple senescence markers, including elevated SA-β-gal activity and upregulated expression of p21Cip1/Waf1 and p16INK4a [253]. Concurrently, COPD patients demonstrate amplified SASP activity, characterized by increased secretion of IL-1, IL-6, CCL2, and MMP9 [254]. Lin et al. [255] revealed that tetrahedral DNA nanostructures promoted clearance of senescent dermal fibroblasts by suppressing the antiapoptotic protein BCL-2 and enhancing BAX expression. In parallel, Yao et al. [256] identified FOXO4 as a novel therapeutic target in cigarette smoke extract (CSE)-induced senescent fibroblasts. A self-assembled DNA nanotube loaded with FOXO4-specific siRNA delivered siRNA into human lung fibroblasts (HFL-1) in a concentration- and time-dependent manner. Crucially, siFOXO4-NT selectively eliminated senescent HFL-1 cells by downregulating BCL-XL expression and reducing the elevated BCL-2/BAX ratio in CSE-induced senescence. Collectively, these findings offer a promising avenue for developing senolytic therapies targeting COPD pathogenesis.

In addition, multiple evidences suggest that retinal diseases are associated with cellular aging, such as upregulation of TGF-β and p21 expression in senescent corneal cells, which in turn promotes the SASP secretion in corneal cells, including TNF-α, IL-6, and macrophage migration inhibitory factor (MIF) [257,258]. An increase in p21 upregulated SnCs was found in the endothelium of Fuchs endothelial dystrophy patients [259]. The levels of senescent macrophages and SASP secretion in the lacrimal gland of graft-versus host disease (GVHD) mice were significantly increased [260], and selective elimination of SnCs improved the function of the lacrimal gland in GVHD [260]. Given the multiple aging-mediated pathological processes, targeted clearance of SnCs may emerge as a novel therapeutic strategy for treating or preventing various ocular disorders. The resveratrol-conjugated gold NPs (RGNPs) developed by Chen et al. [261], which demonstrated remarkable efficacy in inhibiting hydrogen peroxide-induced oxidative damage in lens epithelial cells (LECs). RGNPs effectively alleviated oxidative stress-induced cellular senescence through mechanisms including downregulation of p16 and p21 protein expression, reduction of the BAX/BCL-2 ratio, and inhibition of SASP. Notably, these NPs significantly reduced sodium thiosulfate-induced lens opacities in rats and delayed cataract progression. These findings underscore the potential of targeting cellular senescence therapy for cataracts and other retinal diseases.

6. SWOT analysis and future directions

6.1. SWOT analysis

In terms of the SWOT analysis, the strength of senotherapy lies in its precise targeting of the core mechanisms of aging (Fig. 8), intervening in various aging related diseases from the root [262]. Another key advantage is their broad-spectrum therapeutic potential, where a single senotherapy agent may theoretically address multiple, traditionally distinct, SnCs-driven conditions, embodying the “one drug, multiple comorbidities” concept [263]. The application of nanotechnology further enhances the targeting accuracy, improves drug utilization, and achieves controlled drug release and long-term delivery. NDDS enables precision targeting at the cellular level through surface modifications that specifically recognize biomarkers characteristic of SnCs. As demonstrated, conjugating NPs with CD9 receptor-mediated targeting capability and β-gal triggered cargo release achieved specific targeting of senescent human dermal fibroblasts, thereby reduced the off-target toxicity commonly seen with traditional anti-aging drugs [264]. Complemented by NDDS, senotherapy integrates with conventional treatments (e.g., chemotherapy, radiotherapy, NIR-II photothermal therapy, and gene therapy) and diagnostics (e.g., fluorescence imaging) to create multifunctional theranostic platforms, realizing concurrent therapy and diagnose.

Fig. 8.

SWOT analysis of senotherapy. Figure created with BioRender.com.

Despite encouraging preclinical data, the physiological complexity of humans, heterogeneity of SnCs, and long-term safety issues make this advantage still a high-risk bet. Besides, precise differentiation of pathological SnCs from normal cells remains highly difficult [265]. We also need a new paradigm to evaluate whether tissue regeneration ability, host defense, and cancer surveillance are compromised under long-term intervention, which requires extensive longitudinal safety data and the development of new preclinical models that can simulate the complexity of human aging. Furthermore, it is disheartening that NDDS enhances the feasibility of this strategy by improving targeting, but its complexity also increases the difficulty of conversion. The translation of nanotherapy targeting SnCs from laboratory research to clinical application still faces multiple technical bottlenecks and industrialization challenges [266]. First, the scaled production of NDDS continues to encounter issues such as sensitive reaction conditions and batch-to-batch variations, urgently requiring collaborative breakthroughs between academia and industry. Second, from the clinical perspective, nanotherapy relies on high investment, which may exceed medical insurance coverage, limiting patient accessibility. Additionally, complex intellectual property landscapes lead enterprises to face patent licensing barriers and technology royalty pressures, further squeezing profit margins.

Driven by the global population aging and rising incidence of aging-related diseases, the future of senotherapy presents huge opportunities, creating significant market potential. Opportunities include developing precision senotherapy targeting specific tissues, SnCs subtypes and organelle, combining agents with differing mechanisms (senolytics/senomorphics) and complementary strategies (strategies for combating MSCs aging, NAD⁺ boosters, NIR-II photothermal therapy, gene therapy and, mTOR inhibitors), and exploring the preventative applications of senotherapy for preclinically or early disease pathogenesis [267,268]. For example, MSCs aging is one of the leading theories of organismal aging. The telomeres of MSCs can be extended by telomerase reverse transcriptase activity or resetting the epigenetic clock of cells by regulating the expression of longevity genes such as SIRT1 and FOXO [269]. With the increasing of EV-related clinical trials, MSC derived exosomes may become an alternative therapy for MSC. Aspirin significantly reversed the aging of mesenchymal stem cells by activating endogenous telomerase, thereby maximizing the synergistic anti-aging effect when used in combination with senolytics/senomorphics drugs [270]. In addition to developing more anti-aging drugs, the future opportunity lies in how to use new technologies to achieve precise aging medicine. NDDS should be designed as an integrated diagnosis and treatment system, which can break the boundaries between treatment and diagnosis. It should be noticed that, interdisciplinary convergence offers significant untapped potential, exemplified by artificial intelligence (AI)-driven NDDS revolutionizing drug development. The most critical opportunity lies in leveraging emerging tools, such as single-cell multi-omics to define SnCs subtypes to AI-driven diagnostic theranostics, systematically addressing the weakness of target ambiguity. This deep biological insight is the essential prerequisite for designing the next generation of smart NDDS that can reliably distinguish and eliminate pathological SnCs within specific tissues. Theranostic NDDS capable of imaging SnCs accumulation, SASP intensity, or mitochondrial dysfunction allow real-time monitoring of senescence biology in vivo, which can serve as regulatory-acceptable surrogate endpoints for future regulation. METiS Technologies, for instance, employs reinforcement learning algorithms to optimize lipid nanoparticle (LNP) design, slashing development timelines from years to months. Concurrently, integrating gene editors (e.g., CRISPR-Cas9) with NDDS enables precision engineering of SnCs [271]. For further enhancing efficiency, organ-on-a-chip and organoid platforms provide physiologically relevant screening environments for nanoformulations, dramatically lowering preclinical costs.

The primary threat of senotherapy is the risk of clinical trial failure, where early positive signals may not be replicated in larger, rigorous Phase III trials due to the heterogeneity of diseases and safety concerns. A worse threat is not the failure of a single clinical trial, but the disillusionment experienced by the entire field due to high expectations. Furthermore, navigating potential ethical and societal controversies related to the anti-aging concept is essential.

6.2. Strategic matrix analysis and future directions

SWOT analysis underscores that the fundamental challenge in senotherapy is the translational gap between a potent mechanistic hypothesis and clinical reality. Focusing on leveraging inherent advantages to capitalize on emerging opportunities, strengths-opportunities (SO) strategies lie in the application of senotherapy for clinical urgent indications, such as IPF, OA and AD, which exhibit clarified mechanisms and sufficient clinical evidences. Significantly investing should be paid in the next-generation, tissue selective, and SnCs targeted NDDS. Emphasis should also be placed on the coordinated development with non-invasive diagnostic for the treatment of cellular senescence and the related diseases. Strengths-threats (ST) strategies aim to utilize inherent strengths to mitigate potential threats. Senotherapy requires rigorous, long-term preclinical safety assessments, with particular emphasis on impacts on tissue repair, immune function, and cancer incidence. Researchers and pharmaceutical companies should engage proactively with the regulatory agencies to collaboratively establish viable clinical development pathways and acceptable endpoints, and implement responsible scientific communication to manage public expectations. Weaknesses-opportunities (WO) strategies seek to overcome inherent weaknesses by exploiting opportunities. Researchers should deepen fundamental research into the heterogeneity of SnCs to identify critical, targetable subpopulations and their dependent pathways across diverse disease states. They are also expected to accelerate the discovery and rigorous validation of robust, clinically applicable biomarkers to enable precise patient stratification and personalized treatment regimens. Finally, weaknesses-threats (WT) strategies focus on minimizing weaknesses while avoiding threats. Regulatory agencies are required to establish strict supervision measures for early clinical programs, and enable timely strategy adjustments or termination of high-risk projects based on interim data.

Specifically, future research should employ multidimensional and interdisciplinary approaches to translate aging insights into precise interventions, aiming to shift the paradigm from treating disease to promoting healthy aging. First, target identification has emerged as a crucial direction for aging-related disease in the near future. Second, spatial transcriptomics can map the distribution of SnCs within tissues, clarify their microenvironmental characteristics, and provide critical insights for designing microenvironment-responsive NDDS in personalized nanomedicine strategies, thereby maximizing synergistic effects [272,273]. Additionally, AI-based drug discovery also paves the way for personalized nanomedicine, enabling the accurate design of NDDS for senolytic therapy. Finally, from an ethical perspective, proactive development of rational regulatory strategies is crucial to prevent excessive commercial hype and manage unrealistic expectations regarding outcomes like life extension.

7. Conclusions

Senescence is a systemic degenerative process that involves interactions at multiple levels and pathways, including telomere attrition, DNA damage, epigenetic erosion, mitochondrial dysfunction, SASP, and protein homeostasis imbalance. Corresponding to the mechanisms related to cellular senescence, senotherapies, particularly senolytics and senomorphics, are promising approaches for targeting cellular senescence. Strategies such as NAD⁺ boosters, genes and epigenetic regulation, anti-inflammatory and immunomodulation also show prospects in interventions targeting cellular senescence. Specially, nano-based therapies hold substantial promises for application through programmable designs, such as spatiotemporal co-delivery, cascade-responsive release, and barrier-penetrating targeting. By precisely modifying the physicochemical properties (e.g., size, charge, surface ligands) of the NPs, the NDDS can not only resolve the pharmacokinetic conflicts between senolytics and senomorphics, but also achieve precise spatiotemporal targeting of single carrier multi-target. The clinical translation of products for aging treatment still needs to overcome the challenges of in vivo fate tracking and large-scale production, which will be the primary focus of anti-aging nanomedicine in the coming decade.

CRediT authorship contribution statement

Yumei Wang: Conceptualization, Funding acquisition, Investigation, Writing – original draft, Writing – review & editing. Mingqi Liu: Data curation, Funding acquisition, Investigation, Writing – original draft, Writing – review & editing. Xinzhao Chen: Writing – original draft. Song Wang: Writing – original draft, Writing – review & editing. Jiatong Li: Writing – original draft, Writing – review & editing. Yuman Sun: Writing – original draft, Writing – review & editing. Xuting Zheng: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Jianxiang Zhang: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Heran Li: Conceptualization, Funding acquisition, Project administration, Writing – original draft, Writing – review & editing.

Ethics approval and consent to participate

Not applicable.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82472136 and No.82304423); Liaoning Provincial Youth Science Foundation, Category B (2025-YQ-10); and China Postdoctoral Science Foundation (2025M773544).

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Heran Li reports financial support was provided by National Natural Science Foundation of China. Yumei Wang reports financial support was provided by National Natural Science Foundation of China. Heran Li reports financial support was provided by Liaoning Provincial Youth Science Foundation, Category B. Mingqi Liu reports financial support was provided by China Postdoctoral Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.