Although the introduction of glycerosomes has enriched strategies for efficient transdermal
drug delivery, the inclusion of
cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in
glycerol solution with β-
sitosterol as the stabilizer. Moreover, the transdermal permeation properties of
lappaconitine (LA)-loaded S-glycerosomes and
peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the
lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the
fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional
liposomes. Additionally, treatment with PO-S-glycerosomes alters the
isoform type, number, and composition of
sphingolipids,
glycerophospholipids, glycerolipids, and
fatty acids in the stratum corneum, with the most notable effect observed for
ceramides, the main component of
sphingolipids. Furthermore, the
transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of
xylene-induced
inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of β-
sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum
lipids.