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Choi et al. Cancer Drug Resist. 2026;9:12 Page 13 of 20

Anesthetized (Zoletil + xylazine)
› Drug administration (TRPV4 agonist/antagonist, AQP4 inhibitor, • Increased CSF tracer influx into PVS
CaM inhibitor) • Deeper and greater penetration into cortical parenchyma
› ICM inj. of FL-labeled tracer (Alexa Fluor 555; 6 μL) • Enhanced rostro-caudal distribution (bregma -2 to +1 mm)
› US treatment
› Ex vivo FL micro. (euthanized at 30 min p.i., brain sectioned and • Enhanced influx mediated by the TRPV4-CaM-AQP4 pathway
optically cleared) [MB] • Transient astrocyte swelling due to water influx via AQP4 (20-40 min p.t.)
› Ex vivo confocal micro. (immuno-stained: TRPV4-Alexa Fluor • None • Full recovery of astrocyte volume (65 min p.t.)
488, AQP4/GFAP-Alexa Fluor 633) [Transducer]
• Unfocused
Anesthetized (Zoletil + xylazine) • Fc: 1 MHz
Wu et • Mice (C57BL/6JNarl) › ICM inj. of FL-labeled tracer (Alexa Fluor 555; 6 μL) [Sonication] • Increased CSF tracer influx into PVS at 15 min
al. [64] • Normal
› US treatment • PRF: 1 kHz • Greater tracer infiltration into brain parenchyma
› In vivo FL imaging (0-64 min p.i.; skin incised; dorsal calvarium) • Duty cycle: 1%
• Duration: 5 min
Anesthetized (Zoletil + xylazine) • I SPTA : 3.68 mW·cm (~98
2
› Drug administration (TRPV4 agonist/antagonist) kPa)
› Parenchymal inj. of FL-labeled tracer/human Aβ (Alexa/HiLyte • Reduced residual tracer/Aβ in the parenchymal injection site
Fluor 555; 12 μL; left striatum) • Increased tracer/Aβ drainage to dcLNs
› US treatment • Enhanced waste clearance via a TRPV4-dependent pathway
› Ex vivo FL micro. (3 h p.i.; euthanized, brain sectioned and dcLNs
harvested; both optically cleared)
› Tissue homogenization 80
[MB]
[Preparation: 2-3 weeks before US treatment] • Commercial • Synchronized vessel deformation with US sonication (7.25× higher change in
› Cranial window implantation (scalp incised, skull removed, brain • Size: 1.34 ± 0.28 μm diameter)
covered with agarose, polyester film sealed with epoxy/dental [Transducer] • Enhanced local clearance of injected CSF tracer (1.86× higher intensity, 4.57×
• Mice (female, cement) • Ring-type
Gong et claudin-5-GFP transgenic, [Protocol] • Fc: 0.5 MHz faster clearance rate) 2
al. [39] C57BL/6J background) Anesthetized (ketamine + xylazine) • FWHM: 2 × 10 mm • Significant linear correlation between vessel deformation and tracer clearance (R =
• Normal › ICM inj. of FL-labeled tracer (Alexa Fluor 555; 10 μL) [Sonication] 0.82)
› IV inj. of MBs • PNP: 0.3 MPa • Stronger clearance response in larger vessels: linear regression slopes of
› US treatment (30 min p.i. of tracer) • 1,000 cycles 2.61/0.85/0.24 for large (70-100 μm)/medium (40-70 μm)/small (10-40 μm)
› Live in vivo two-photon micro. • PRF 5 Hz vessels
• Duration: 2 min