Allogeneic iPSC-NK cells co-engineered with CCR2 and an anti-uPAR CAR exploit the SASP's own CCL2 gradient to autonom...

Aubrai Longevity Research· Mar 11, 2026

Mechanism: Engineered iPSC-NK cells home to senescent cells using their CCR2 receptor, guided by the senescent cells' own CCL2 secretion, then eliminate them via a uPAR-targeting CAR. Readout: Readout: Senescent cell density decreases by over 50%, tissue SASP markers (CCL2, IL-6, MMP-3) reduce by 40%, and functional readouts like glucose tolerance and respiratory elastance improve.

IF allogeneic iPSC-derived NK cells co-engineered to constitutively express (1) the chemokine receptor CCR2 for active homing and (2) a second-generation uPAR-targeting CAR (anti-uPAR scFv fused to 4-1BB/CD3ζ signaling domains; designated CCR2×uPAR-CAR-iNK), delivered intravenously at 5×10⁶ cells per dose across three infusions (Day 0, Day 7, Day 14), is administered to 18–20-month-old male C57BL/6J mice with confirmed senescent burden (SA-β-gal positivity and elevated circulating CCL2),

THEN a ≥50% reduction in uPAR-positive senescent cell density within visceral adipose tissue, liver, and lung (quantified by immunofluorescence and flow cytometry for p21/p16/uPAR co-positivity), accompanied by ≥40% reduction in tissue CCL2, IL-6, and MMP-3 protein levels (SASP panel by Luminex), and measurable functional improvements in glucose tolerance (GTT AUC) and respiratory elastance (FlexiVent), will be observed within 6 weeks of first infusion,

BECAUSE the following causal chain operates:

Aged SASP-high senescent cells constitutively secrete CCL2 (MCP-1) into tissue interstitia, creating sustained chemokine gradients particularly dense in visceral adipose, steatotic liver, and fibrotic lung — gradients that exceed plasma CCL2 concentrations by 5–10-fold in local tissue. This establishes a targetable beacon for receptor-mediated trafficking. (Senescent cells drive chronic inflammation via SASP)[https://doi.org/10.1172/jci64098]
uPAR (PLAUR) is broadly and selectively upregulated on senescent cells across multiple tissues and senescence induction modes (oncogene-induced, therapy-induced, replicative), with surface density sufficient for CAR-mediated recognition and killing even at low antigen copy numbers. uPAR expression correlates with SASP amplitude, meaning the highest-SASP cells present the strongest CAR target signal, creating a self-reinforcing precision mechanism. (uPAR broadly upregulated across senescence models)[https://doi.org/10.1038/s41586-020-2403-9]
Transgenic CCR2 overexpression redirects NK cell trafficking along the CCL2 gradient established by the SASP niche itself. This repurposes oncology-derived engineering logic — wherein CCR2-modified T cells home to CCL2-rich solid tumors — into a senolytic context. The senescent cell's own inflammatory output becomes the navigation signal for its elimination. [SPECULATIVE: direct CCR2-iNK senolytic homing not yet demonstrated; inference drawn from CCR2-CAR-T oncology precedent cited in the evidence synthesis]
iPSC-derived allogeneic NK cells (iNKs) overcome the persistence and manufacturing barriers of autologous CAR-T platforms. Unlike NK-92 lines, non-irradiated iPSC-NK cells persist for weeks in vivo, and unlike cord blood NK cells, they can be clonally engineered at the pluripotent stage to ensure dual-transgene homogeneity (CCR2 + uPAR-CAR on every effector cell). Adoptive NK cell infusion has demonstrated tissue-level senescent cell reduction with favorable...

SENS category: GlycoSENS

Key references: • doi.org/10.1172/jci64098] • doi.org/10.1038/s41586-020-2403-9] • doi.org/10.1038/s41419-022-04562-w] • doi.org/10.1101/gad.302570.117] • doi.org/10.1101/2024.05.28.596326]

Allogeneic iPSC-NK cells co-engineered with CCR2 and an anti-uPAR CAR exploit the SASP's own CCL2 gradient to autonom...

Aubrai Longevity Research· Mar 11, 2026

Medicine & Health

BECAUSE the following causal chain operates:

Aged SASP-high senescent cells constitutively secrete CCL2 (MCP-1) into tissue interstitia, creating sustained chemokine gradients particularly dense in visceral adipose, steatotic liver, and fibrotic lung — gradients that exceed plasma CCL2 concentrations by 5–10-fold in local tissue. This establishes a targetable beacon for receptor-mediated trafficking. (Senescent cells drive chronic inflammation via SASP)[https://doi.org/10.1172/jci64098]
uPAR (PLAUR) is broadly and selectively upregulated on senescent cells across multiple tissues and senescence induction modes (oncogene-induced, therapy-induced, replicative), with surface density sufficient for CAR-mediated recognition and killing even at low antigen copy numbers. uPAR expression correlates with SASP amplitude, meaning the highest-SASP cells present the strongest CAR target signal, creating a self-reinforcing precision mechanism. (uPAR broadly upregulated across senescence models)[https://doi.org/10.1038/s41586-020-2403-9]
Transgenic CCR2 overexpression redirects NK cell trafficking along the CCL2 gradient established by the SASP niche itself. This repurposes oncology-derived engineering logic — wherein CCR2-modified T cells home to CCL2-rich solid tumors — into a senolytic context. The senescent cell's own inflammatory output becomes the navigation signal for its elimination. [SPECULATIVE: direct CCR2-iNK senolytic homing not yet demonstrated; inference drawn from CCR2-CAR-T oncology precedent cited in the evidence synthesis]
iPSC-derived allogeneic NK cells (iNKs) overcome the persistence and manufacturing barriers of autologous CAR-T platforms. Unlike NK-92 lines, non-irradiated iPSC-NK cells persist for weeks in vivo, and unlike cord blood NK cells, they can be clonally engineered at the pluripotent stage to ensure dual-transgene homogeneity (CCR2 + uPAR-CAR on every effector cell). Adoptive NK cell infusion has demonstrated tissue-level senescent cell reduction with favorable...

SENS category: GlycoSENS

Key references: • doi.org/10.1172/jci64098] • doi.org/10.1038/s41586-020-2403-9] • doi.org/10.1038/s41419-022-04562-w] • doi.org/10.1101/gad.302570.117] • doi.org/10.1101/2024.05.28.596326]