Ferroptotic senolysis via SA-β-gal-activated HK-PCGC produces superior SASP shutdown, immunogenic macrophage recruitm...

IF HK-PCGC (SA-β-galactosidase-activated Ce6 photosensitizer conjugated to ferritin nanocage; administered intravenously at a dose range informed by prior ferritin-nanoparticle pharmacokinetics, with subsequent near-infrared light activation targeting lung and liver fields) is administered to aged (22–24 month) male and female C57BL/6J mice and compared head-to-head against navitoclax (ABT-263; 50 mg/kg oral gavage, 5 days on/16 days off, standard senolytic protocol),

THEN HK-PCGC-treated mice will exhibit: (1) equivalent or superior senescent cell clearance in lung and liver (≥40% reduction in p16^INK4a^+/SA-β-gal+ cells versus vehicle); (2) significantly lower residual circulating SASP factors (IL-6, IL-8/KC, MMP-3, GDF-15) at 4 and 12 weeks post-treatment versus navitoclax (predicted ≥50% lower area-under-curve for SASP panel); (3) absent or minimal thrombocytopenia (platelet counts within 15% of young-mouse reference, versus navitoclax-associated >50% platelet loss); (4) superior secondary macrophage-mediated bystander senolysis (increased phagocytic index of tissue-resident macrophages, elevated M1-skewing markers iNOS/TNF-α transiently then resolving, reduced anti-phagocytic CD47 "don't eat me" signaling on residual senescent cells); and (5) superior long-term physical fitness and transcriptomic rejuvenation scores (grip strength, rotarod, treadmill endurance; bulk RNA-seq aging clock reversal in lung/liver),

BECAUSE the following mechanistic chain operates:

1. Senescent cell iron overload creates ferroptosis vulnerability. Senescent cells accumulate labile iron due to lysosomal dysfunction (impaired ferritinophagy), upregulated ferritin heavy/light chain expression as part of the senescence secretome, and elevated transferrin receptor-1 (TfR1) surface expression — creating a pro-ferroptotic intracellular milieu not present in proliferating or quiescent non-senescent neighbors. [SPECULATIVE linkage to HK-PCGC specificity, but consistent with known senescent cell iron biology and the mechanistic rationale for using ferritin as the nanocarrier]

2. SA-β-gal-dependent Ce6 activation ensures senescence-selective photosensitizer release. HK-PCGC exploits the lysosomal SA-β-gal activity that is the canonical senescence biomarker: the galactose-masked Ce6 photosensitizer is cleaved exclusively within SA-β-gal-positive lysosomes, concentrating reactive photosensitizer in senescent cells. Upon light activation, Ce6 generates singlet oxygen (^1O₂) and superoxide, initiating lipid peroxidation (primarily 4-HNE and malondialdehyde adducts on phosphatidylethanolamine). Ferritin iron released from the nanocage participates in Fenton-type reactions amplifying lipid radical chain propagation — constituting mechanistic ferroptosis (GPX4-suppressible, ferrostatin-1-rescuable). [Core HK-PCGC mechanism as described in the Research Context]

3. **Ferroptotic lipid peroxidation disrupts the ER-Golgi secretory apparatus required for SASP maintenance BE...

SENS category: GlycoSENS