Dendrimeric liquid crystals actively modulate cavitation, skin transport pathways, and drug fate during low-frequency sonophoresis.

This work presents the first exploration of dendrimeric liquid crystals (DLCs) as dual-function platforms for low-frequency ultrasound (LFU)-mediated skin delivery. We hypothesized that, beyond acting as drug reservoirs, DLCs could actively modulate cavitation, the formation of localized transport regions (LTRs), and the intradermal microenvironment governing drug partitioning after insonation. Tetrasulfonated zinc phthalocyanine (ZnPcS4), a hydrophilic photosensitizer with poor intrinsic permeability, was selected as a model drug. NMR confirmed the supramolecular association between the PAMAM G2 dendrimer and a fluorinated acid. Polarized light microscopy and SAXS/WAXS demonstrated that when dispersed in a hydroxyethyl cellulose (HEC) hydrogel, DLCs formed stable and highly organized liquid crystalline domains. Drug incorporation and LFU exposure promoted additional rearrangements without disrupting matrix integrity, thereby supporting carrier robustness. Functionally, under LFU, DLC:HEC produced a complete rupture of the aluminum foil, whereas viscosity-matched HEC caused only partial damage, indicating stronger cavitation. This resulted in an approximately threefold expansion of the skin LTR surface coverage (24% vs. 7%). Despite this, DLCs strongly retained ZnPcS4, passively releasing <5% of it; 1 min LFU increased the release by approximately fourfold. In the skin, during direct drug formulation insonation, DLC:HEC enhanced drug deposition in the stratum corneum by nearly one order of magnitude compared to HEC. After LFU pretreatment with drug-free DLC:HEC, DLC-associated domains likely persisted within the LTRs formed in the stratum corneum, establishing a shared microenvironment for subsequently applied formulations. Under these conditions, no statistically significant differences in ZnPcS4 skin distribution or receptor delivery were observed between the HEC and DLC-containing donors, indicating that transport was primarily governed by the preformed LFU-induced pathways and the interaction environment established within the modified stratum corneum. Overall, DLCs actively shape both pathway generation and drug fate in LFU-treated skin, providing a versatile strategy for balancing local retention and transdermal transport.