Various lipid nanovesicular systems have been developed with the aim to enhance the delivery of drugs via transdermal route. However, their clinical applications are often limited due to the barrier nature of skin and lack of flexibility. Herein, we have modified the conventional nanoliposomes (CLs) prepared by a thin-film hydration method by the addition of a polyol (glycerol) to form novel lipid nanovesicular structures termed 'POLYOLIPOSOMES' (PLs). They were further named as PL-B (before film formation) and PL-A (after film formation), depending on the stage of glycerol addition during production. Optimized CLs, PL-B and PL-A showed spherical nanovesicles and hydrodynamic diameter of 181.3 ± 4.11 nm, 114.2 ± 7.21 nm and 170.2 ± 6.51 nm, respectively. PLs showed significantly higher % entrapment efficiency and deformability index in comparison to CLs, indicating their higher flexibility. Furthermore, DSC and attenuated total relection (ATR)-Fourier transform infrared (FTIR) studies revealed the intercalation of glycerol into the lipid bilayer of PLs and interaction between nanovesicles and skin. Moreover, ex vivo and in vivo skin permeation studies confirmed the enhanced drug delivery of PLs via the transdermal route. Taken together, these results illustrate the potential of PLs as a novel lipid nanovesicular system for drug delivery via the transdermal route for both systematic (PL-B) as well as cutaneous diseases (PL-A).