Search Results (170)

Drought is one of the most severe abiotic stresses limiting agricultural productivity and threatening global food security. As the central organelle responsible for photosynthesis and stress perception, the chloroplast is highly sensitive to drought, and its structural and functional stability directly determines plant adaptability. Recent studies have revealed that chloroplasts undergo pronounced ultrastructural alterations under drought stress, including thylakoid membrane shrinkage, disorganization of grana stacks, and accumulation of reactive oxygen species (ROS). Excessive ROS production causes oxidative damage to lipids, proteins, and nucleic acids, whereas moderate ROS levels act as retrograde signals to regulate nuclear gene expression. In parallel, calcium (Ca²⁺) oscillations and retrograde signaling pathways—such as those mediated by GENOMES UNCOUPLED PROTEIN1 (GUN), 3′-phosphoadenosine-5′-phosphate (PAP), and Methylerythritol cyclodiphosphate (MecPP)—integrate chloroplast-derived stress cues with nuclear responses. To counteract drought-induced damage, plants activate a series of antioxidant systems—both enzymatic (Superoxide Dismutase (SOD), Ascorbate Peroxidase (APX), Catalase (CAT)) and non-enzymatic (Ascorbic Acid (ASA), (Glutathione) GSH, tocopherols, carotenoids)—along with protective proteins such as fibrillins (FBNs) and WHIRLYs that stabilize thylakoid and membrane structures. In addition, autophagy and plastid degradation pathways selectively remove severely damaged chloroplasts to maintain cellular homeostasis. Exogenous substances, including melatonin, 5-aminolevulinic acid (ALA), and Zinc oxide (ZnO) nanoparticles, have also been shown to enhance chloroplast stability and antioxidant capacity under drought stress. In this review, we discuss the structural and functional changes in chloroplasts, signaling networks, and protective repair mechanisms under drought stress. Furthermore, we highlight future research prospects for enhancing plant stress resilience through multi-omics integration, application of functional regulators, and molecular design breeding. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article

Grazing pressure (GP) was a key factor influencing net primary productivity (NPP) in pasturelands and was characterized by two indicators: grazing intensity (GI) and grazing density (GD). However, current research has not yet clarified whether the mechanisms linking GP to NPP varied by season, or whether seasonal thresholds of grazing pressure existed. This study employed the Carnegie–Ames–Stanford Approach (CASA) model to estimate NPP over eight time periods between 2010 and 2024 for three seasonal pastures (spring–autumn, summer, and winter) in the study area. Estimation accuracy was evaluated by comparing our NPP estimates with existing NPP products. Trends in NPP and their significance were analyzed using the Sen–MK method, followed by further examination of spatiotemporal variations in NPP across the three seasonal pastures. Subsequently, by comparing two grazing pressure indicators (GI and GD), we identified the optimal metric to represent GP and, on this basis, analyzed the spatiotemporal variations and threshold dynamics of pasture NPP across three seasons under the influence of GP. Results indicated that the CASA model achieved R² > 0.90 for multi-year NPP estimation, with RMSE ranging from 27 to 45 g C m⁻² y⁻¹. Spring–autumn and winter pastures exhibited pronounced slope changes and intense spatiotemporal NPP variations, whereas summer pastures showed insignificant slope changes and stable spatiotemporal NPP patterns. Of the two GP indicators, the GD metric developed herein more effectively characterized grazing pressure across the study area. Across the three seasonal pastures, a consistent negative feedback between GD and NPP was evident; however, its strength differed markedly, with spring–autumn and winter pastures exhibiting greater NPP sensitivity to GD. The GD thresholds for spring–autumn, summer, and winter pastures in the study area were approximately 900, 700, and 5000 sheep km⁻², respectively. Exceeding these thresholds led to degradation, while falling below them promoted recovery. The study revealed a threshold-mediated negative feedback between GD and NPP across seasonal pastures, quantified season-specific upper bounds of carrying capacity, and provided an evidence base for zoned rest/rotational grazing and GD regulation along the northern slope of the Tianshan Mountains. Full article

Hulun Lake, the largest freshwater lake in the Eurasian steppe, is a critically climate-sensitive water body facing severe ecological threats. This systematic review synthesizes multidisciplinary evidence from 1961 to 2025 to examine the characteristics and drivers of its water environment and quality evolution. The findings reveal that the primary driver of the lake’s hydrological degradation shifted from natural climate variability to anthropogenic land-use change around 1998. While ecological water diversion has partially alleviated water scarcity, it also introduces a significant external nutrient load, creating a paradox where increased water volume coincides with aggravated eutrophication. Furthermore, overgrazing in the catchment not only enhances conventional runoff pollution but also facilitates a unique “tumbleweed-mediated cross-media pollution” pathway. This review concludes that the restoration of Hulun Lake necessitates a shift from singular water quantity regulation to an integrated management strategy that concurrently addresses water quantity, quality, and aquatic ecosystem health. The insights gained are crucial for informing the sustainable management of Hulun Lake and other inland lakes in cold, arid regions under global change. Full article

Nitric oxide (NO), a reactive nitrogen species (RNS), plays a role in multiple biological functions and signal transduction. However, the mechanisms by which NO counteracts stress tolerance in microbes have been poorly explored. In addition, the decomposition of salty food waste poses a significant challenge for food-degrading microbes. Therefore, we investigated how S-nitrosocysteine (CysNO) affects the cellular salt stress response of Burkholderia vietnamiensis TVV75, a strain isolated from a commercial food waste composite. Under the additional 2% NaCl treatment, increased reactive oxygen species (ROS) inhibited bacterial cell growth and viability. In contrast, CysNO treatment alleviated the cellular ROS levels and growth inhibition by augmenting the superoxide dismutase (SOD) and catalase (CAT) activities. CysNO supplementation also promotes the nitrate reduction pathway in B. vietnamiensis TVV75 under salt stress, suggesting NO-mediated nitrogen metabolism for microbial adaptation to salt stress. Furthermore, CysNO restored the intracellular lipid-degrading lipase enzyme activities, which were compromised by salt stress alone. This restoration was accompanied by a concentration-dependent increase in the relative expression of the lipA (lipase A) and ELFPP (esterase lipase family protein) genes. These results suggest that external NO supplementation can regulate redox balance, nitrate reduction, and lipase activity to maintain microbial cell growth in high-salt environments, pinpointing a NO-dependent salt stress adaptation strategy for salt-sensitive microbes involved in food waste decomposition. Full article

Tyrosine (Tyr) degradation is a crucial pathway in animals. However, its role in plants remains to be examined. Fumarylacetoacetate hydrolase (FAH) is the final enzyme involved in Tyr degradation. Studies of a mutant of the SHORT-DAY SENSITIVE CELL DEATH 1 (SSCD1) gene encoding FAH in Arabidopsis have shown that blockage of this pathway results in the accumulation of Tyr metabolites, thereby inducing cell death under short-day conditions. Seed dormancy is a critical trait which is regulated by endogenous and environmental cues, among which abscisic acid (ABA) and gibberellin (GA) are the primary effectors. ABA induces seed dormancy, whereas GA releases seed dormancy. In this study, sscd1 seeds displayed deep dormancy and hypersensitivity to the GA biosynthesis inhibitor paclobutrazol, but not to ABA during germination. However, exogenous GA₃ could not completely recover dormancy or germination of sscd1 seeds. Moreover, GA₃ level was reduced, which was consistent with the decreased expression of GA3-oxidase 1 in imbibed sscd1 seeds. Furthermore, SSCD1 acted upstream of RGA-LIKE 2. Eliminating the accumulation of Tyr metabolites by inhibiting homogentisate dioxygenase, an enzyme upstream of FAH, completely rescued the phenotype of sscd1 seeds. Additionally, germination of sscd1 seeds was hypersensitive to FAH deficiency-induced accumulation of succinylacetone, which is a Tyr metabolite. These findings suggest that FAH deficiency in sscd1 causes accumulation of Tyr metabolites, thereby disrupting GA biosynthesis and signaling. This resulted in deep dormancy and hypersensitivity to paclobutrazol during germination and highlights the important role of the Tyr degradation pathway in GA-mediated seed dormancy and germination. Full article

Background and Objectives: Myofibroblast apoptosis resistance and excessive extracellular matrix (ECM) deposition are central drivers of the irreversibility of pulmonary fibrosis, and both are mechanistically linked to autophagy impairment. Phaseoloidin is a bioactive compound derived from Entada phaseoloides. This study aimed to investigate the therapeutic potential of Phaseoloidin in bleomycin-induced pulmonary fibrosis and its underlying mechanisms. Methods:In vivo, the antifibrotic effects of Phaseoloidin were evaluated using a bleomycin-induced pulmonary fibrosis mouse model in male C57/BL mice. To further elucidate the mechanisms by which Phaseoloidin counteracts fibrosis, in vitro experiments were conducted using primary lung fibroblasts. Results: In vitro experiments showed that Phaseoloidin could activate the AMPK/mTOR pathway in autophagy-deficient myofibroblasts, effectively reversing autophagic defects and promoting collagen degradation. This autophagy activation selectively degraded PTPN13, a negative regulator of apoptosis, thereby enhancing the sensitivity of myofibroblasts to FasL-induced apoptosis and further facilitating fibrosis resolution. After AMPK gene knockout, the pro-autophagic effect of Phaseoloidin completely disappeared, and both collagen clearance and apoptosis recovery were blocked. In vivo experiments confirmed that Phaseoloidin exerted antifibrotic effects by activating AMPK-mediated autophagy in myofibroblasts, which significantly ameliorated pulmonary fibrosis. Conclusions: Phaseoloidin exerts a dual mechanism by activating AMPK-mediated autophagy in myofibroblasts: first, degrading PTPN13 to reverse myofibroblast apoptosis resistance; second, enhancing ECM turnover. These findings indicate that Phaseoloidin is a promising novel therapeutic candidate for pulmonary fibrosis. Full article

Monascus pigments (MPs), natural food colorants produced by Monascus spp., have been traditionally used in China and Southeast Asia. Our prior work demonstrated that altered cell wall architecture in M. purpureus M9 significantly enhances pigment synthesis and secretion, although biosynthetic regulation under combined cell wall stress and acidic conditions remains unexplored. This study employed comparative transcriptomics to investigate coordinated regulation of MP production by pH stress and modified cell wall polysaccharides in wild-type (M9-WT) and UDP-galactopyranose mutase-deficient (M9-KO) strains at pH 5.0 and 3.0. At pH 5.0, MpglfA knockout enhanced MP secretion through cell wall restructuring involving differential expression total 67 genes (DEGs) of primary metabolism. Acidic stress (pH 3.0) significantly increased DEGs (168 up/643 down) in M9-KO versus M9-WT, inducing amino acid/fatty acid degradation pathways that generate MP precursors (acetyl-CoA/propionyl-CoA) and accelerating metabolic transition toward secondary metabolism. Concurrently, M9-KO adopted survival strategies featuring growth suppression and acid stress pathway activation to coordinate osmotic adaptation. Glucan synthase genes exhibited greater pH sensitivity than galactomannan-related genes, while MP biosynthetic genes were transcriptionally repressed in M9-KO under higher acidity. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment and the series test of cluster confirmed that primary metabolic pathways, particularly nitrogen/carbon metabolism, critically regulate MP biosynthesis. Transcriptomic analysis under limited pH regimes revealed that antagonistic regulators ROX1 and SPT15 mediated pH-responsive transcriptional reprogramming, potentially regulating specific MP biosynthesis (e.g., monascus orange pigments). This work established theoretical foundations for manipulating cell wall composition to enhance MP production efficiency. Full article

Anecdotal reports have recently circulated suggesting that intramuscular injection of bacteriostatic saline (BS)—which contains benzyl alcohol (BnOH)—can reverse botulinum toxin type A (BoNTA)-induced brow ptosis. Given the well-established intracellular persistence of BoNTA’s light chain and its irreversible cleavage of SNAP-25, such rapid functional recovery challenges existing pharmacological understanding. This study employed high-resolution pharmacokinetic/pharmacodynamic (PK/PD) modelling using the AesthetiSim™ platform to systematically evaluate this hypothesis. A total of 30,000 virtual patients were randomized to receive BoNTA alone, BoNTA followed by BS injection, or BoNTA followed by normal saline (NS) at Day 7. The model incorporated BoNTA diffusion, internalization, SNAP-25 cleavage, neuromuscular output, and transient BS effects on membrane permeability and endosomal trafficking. Simulated recovery trajectories were tracked over 90 days. The primary outcome, time to 80% restoration of baseline frontalis muscle force (T₈₀), averaged 42.0 days in the BoNTA-only group and 35.5 days in the BS group (Δ = −6.5 days; p < 0.001). Only 13.9% of BS-treated patients reached the T₈₀ threshold by Day 30. Partial reactivation (T₃₀) occurred earlier with BS (21.8 ± 5.3 days vs. 27.3 ± 4.9 days), and the area under the effect curve (AUEC) was increased by 9.7%, reflecting higher overall muscle function over time. In molecular simulations, BnOH produced a minor rightward shift in the BoNTA–SNAP-25 dissociation curve, but receptor occupancy remained above 90% at therapeutic toxin concentrations, suggesting no meaningful impairment of binding affinity. A global Sobol sensitivity analysis demonstrated that the primary driver of recovery kinetics was intracellular LC degradation (49% of T₈₀ variance), while BS-modulated extracellular parameters collectively contributed less than 20%. These findings indicate that BS does not reverse the molecular action of BoNTA but may transiently influence recovery kinetics via non-receptor-mediated pathways such as increased membrane permeability or altered vesicular trafficking. The magnitude and variability of this effect do not support the notion of a true pharmacologic reversal. Instead, these results emphasize the need for mechanistic scrutiny when evaluating rapid-reversal claims, particularly those propagated through anecdotal or social media channels without supporting biological plausibility. Full article

Cytokinins (CKs) are central regulators of leaf senescence, yet their cultivar-specific functions in cereals remain insufficiently understood. Here, we examined dark-induced senescence (DIS) in three barley (Hordeum vulgare L.) cultivars: Carina, Lomerit, and Bursztyn, focusing on responses to exogenous benzyladenine (BA) and inhibition of endogenous CK biosynthesis via the mevalonate (MVA) pathway using lovastatin (LOV). Bursztyn, a winter cultivar, displayed a previously uncharacterized stay-green phenotype, characterized by delayed chlorophyll and protein degradation and reduced sensitivity to BA with respect to chlorophyll retention. In contrast, Carina (spring) senesced rapidly but exhibited strong responsiveness to BA. Lomerit (winter) showed an intermediate phenotype, combining moderate natural resistance to senescence with clear responsiveness to BA. CK application suppressed SAG12 cysteine protease accumulation in all cultivars, serving as a marker of senescence and N remobilization, stabilized photosystem II efficiency, preserved photosynthetic proteins, and alleviated oxidative stress without promoting excessive energy dissipation. Although BA only partially mitigated the decline in net CO₂ assimilation, it sustained ribulose-1,5-bisphosphate regeneration, supported electron transport, and stabilized Rubisco and Rubisco activase. Moreover, LOV-based inhibition of the MVA pathway of CK biosynthesis revealed that endogenous CK contributions to senescence delay were most pronounced in Lomerit, moderate in Bursztyn, and negligible in Carina, indicating genotype-specific reliance on MVA-versus methylerythritol phosphate (MEP) pathway-derived CK pools. Collectively, these findings identify Bursztyn as a novel genetic resource for stay-green traits and demonstrate that BA delays DIS primarily by maintaining photosynthetic integrity and redox balance. The results highlight distinct regulatory networks shaping CK-mediated senescence responses in cereals, with implications for improving stress resilience and yield stability. Full article

Background: Bradykinin (BK) is an inflammatory mediator. The degradation of labeled synthetic BK in biofluids can be used to report on the activity of angiotensin-converting enzyme (ACE) and basic carboxypeptidases N and CBP2, for which the neuropeptide is a substrate. Clinical studies have shown significant changes in the serum activity of these enzymes in patients with inflammatory diseases. Methods: Here, we investigated variation in the cleavage of dabsylated synthetic BK (DBK) in serum and the formation of the major enzymatic fragments using a thin-layer chromatography-based neuropeptide reporter assay (NRA) in a large cohort of healthy volunteers from the international human Personal Omics Profiling consortium based at Stanford University. Results: Four major outcomes were reported. First, a set of NRA reference data for the healthy population was delivered, which is important for future investigations of patient sera. Second, it was shown that the measured serum degradation capacity for DBK was significantly higher in males than in females. There was no significant correlation of the NRA results with ethnicity, body mass index or overnight fasting. Third, a batch effect was noted among sampling sites (HUPO conferences). Thus, we used subcohorts rather than the entire collection for data mining. Fourth, as the low-cost and robust NRA is sensitive to enzyme activity, it provides such a necessary quick test to eliminate degraded and/or otherwise questionable samples. Conclusions: The results reiterate the critical importance of a high level of standardization in pre-analytical sample collection and processing—most notably, sample quality should be evaluated before conducting any large and expensive omics analyses. Full article

Ultrasound-responsive nanomaterials represent a promising approach for achieving non-invasive and localized drug delivery within tumor microenvironments. In this study, we developed a piezocatalysis-assisted hydrogel system that integrates reactive oxygen species (ROS) generation with stimulus-responsive drug release. The platform combines piezoelectric barium titanate (BTO) nanoparticles with a ROS-sensitive hydrogel matrix, forming an ultrasound-activated dual-function therapeutic system. Upon ultrasound irradiation, the BTO nanoparticles generate ROS—predominantly hydroxyl radicals (^•OH) and singlet oxygen (¹O₂)—through the piezoelectric effect, which triggers hydrogel degradation and facilitates the controlled release of encapsulated therapeutic agents. The composition and kinetics of ROS generation were evaluated using radical scavenging assays and fluorescence probe techniques, while the drug release behavior was validated under simulated oxidative environments and acoustic fields. Structural and compositional characterizations (TEM, XRD, and XPS) confirmed the quality and stability of the nanoparticles, and cytocompatibility was assessed using 3T3 fibroblasts. This synergistic strategy, combining piezocatalytic ROS generation with hydrogel disintegration, demonstrates a feasible approach for designing responsive nanoplatforms in ultrasound-mediated drug delivery systems. Full article

Cardiovascular and metabolic disorders significantly reduce healthspan and lifespan, with oxidative stress being a major contributing factor. Oxidative stress, marked by elevated reactive oxygen species (ROS), disrupts cellular and systemic functions. One proposed mechanism involves TRPM2 (Transient Receptor Potential Melastatin2)-dependent Ca²⁺ dysregulation. These channels, activated by ROS (via ADP-ribose), not only respond to ROS but also amplify it, creating a self-sustaining cycle. Recent studies suggest that TRPM2 activation triggers a cascade of signals from intracellular organelles, enhancing ROS production and affecting cell physiology and viability. This review examines the role of TRPM2 channels in oxidative stress-associated cardiovascular and metabolic diseases. Oxidative stress induces TRPM2-mediated Ca²⁺ influx, leading to lysosomal damage and the release of Zn²⁺ from lysosomal stores to the mitochondria. In mitochondria, Zn²⁺ facilitates electron leakage from respiratory complexes, reducing membrane potential, increasing ROS production, and accelerating mitochondrial degradation. Excess ROS activates PARP1 in the nucleus, releasing ADP-ribose, a TRPM2 agonist, thus perpetuating the cycle. Lysosomes act as Ca²⁺-sensitive signalling platforms, delivering toxic Zn²⁺ signals to mitochondria. This represents a paradigm shift, proposing that the toxic effects of Ca²⁺ on mitochondria are not direct, but are instead mediated by lysosomes and subsequent Zn²⁺ release. This cycle exhibits a ‘domino’ effect, causing sequential and progressive decline in the function of lysosomes, mitochondria, and the nucleus—hallmarks of ageing and oxidative stress-related cardiovascular and metabolic diseases. These insights could lead to new therapeutic strategies for addressing the widespread issue of cardiovascular and metabolic diseases. Full article

The endothelial glycocalyx (GCX) plays a crucial role in vascular health and integrity and influences many biochemical activities through mechanotransduction, in which heparan sulfate (HS) plays a major role. Endothelin-1 (ET-1) is a potent vasoregulator that binds to the endothelin B receptor (ETB) on endothelial cells (ECs), stimulating vasodilation, and to the endothelin A receptor on smooth muscle cells, stimulating vasoconstriction. While the shear stress (SS) dependence of ET-1 and HS is well documented, there is limited research documenting the SS dependence of the ETB. Understanding the SS dependence of the ETB is crucial for clarifying the role of hemodynamic forces in the endothelin system. We hypothesize that GCX HS regulates the expression of the ETB on the EC surface in an SS-dependent manner. Human lung microvascular ECs were exposed to SS in a parallel-plate flow chamber for 12 h. Damage to the GCX was simulated by treatment with 15 mU/mL heparinase-III during SS exposure. Immunostaining and qPCR were used to evaluate changes in ET-1, ETB, and HS expression. Results indicate that ETB expression is SS sensitive, with at least a 1.3-fold increase in ETB protein expression and a 0.6 to 0.4-fold-change decrease in ETB mRNA expression under SS. This discrepancy suggests post-translational regulation. In some cases, enzymatic degradation of HS attenuated the SS-induced increase in ETB protein, reducing the fold-change difference to 1.1 relative to static controls. This implies that ETB expression may be partially dependent on HS-mediated mechanotransduction, though inconclusively. Furthermore, ET-1 mRNA levels were elevated two-fold under SS without a corresponding rise in ET-1 protein expression or significant impact from HS degradation, implying that post-translational regulation of ET-1 occurs independently of HS. Full article

Background/Objectives: PEGylated liposomes are widely recognized for their biocompatibility and capacity to extend systemic circulation via “stealth” properties. However, the PEG corona often limits tumor penetration and cellular internalization. Targeting matrix metalloproteinase-2 (MMP-2), frequently upregulated in breast cancer stroma, presents an opportunity to enhance tissue-specific drug delivery. In this study, we engineered MMP-2-responsive GPLGVRG peptide-modified cleavable PEGylated liposomes for targeted paclitaxel (PTX) delivery. Methods: Molecular docking simulations employed the MMP-2 crystal structure (PDB ID: 7XJO) to assess GPLGVRG peptide binding affinity. A cleavable, enzyme-sensitive peptide-PEG conjugate (Chol-PEG_2K-GPLGVRG-PEG_5K) was synthesized via small-molecule liquid-phase synthesis and characterized by ¹H NMR and MALDI-TOF MS. Liposomes incorporating this conjugate (S-Peps-PEG_5K) were formulated to evaluate whether MMP-2-mediated peptide degradation triggers detachment of long-chain PEG moieties, thereby enhancing internalization by 4T1 breast cancer cells. Additionally, the effects of tumor microenvironmental pH (~6.5) and MMP-2 concentration on drug release dynamics were investigated. Results: Molecular docking revealed robust GPLGVRG-MMP-2 interactions, yielding a binding energy of −7.1 kcal/mol. The peptide formed hydrogen bonds with MMP-2 residues Tyr A:23 and Arg A:53 (bond lengths: 2.4–2.5 Å) and engaged in hydrophobic contacts, confirming MMP-2 as the primary recognition site. Formulations containing 5 mol% Chol-PEG_2K-GPLGVRG-PEG_5K combined with 0.15 µg/mL MMP-2 (S-Peps-PEG_5K +MMP) exhibited superior internalization efficiency and significantly reduced clonogenic survival compared to controls. Notably, acidic pH (~6.5) induced MMP-2-mediated cleavage of the GPLGVRG peptide, accelerating S-Peps-PEG_5K dissociation and facilitating drug release. Conclusions: MMP-2-responsive, cleavable PEGylated liposomes markedly improve PTX accumulation and controlled release at tumor sites by dynamically modulating their stealth properties, offering a promising strategy to enhance chemotherapy efficacy in breast cancer. Full article