We studied lipid aggregate penetration through nanoporous, semipermeable barriers by direct transport measurements in vitro and with the confocal laser scanning microscopy of the Skin in vivo. We found that it is necessary to use mixed lipid bilayers with a low resistance to permeabilization and high flexibility to overcome narrow, normally confining pores. Partial molecular demixing in the stressed vesicle bilayer serves both purposes. An aggregate comprising a suitable blend of amphipats (Transfersome, Tfs) is, therefore, extremely deformable and easily crosses even very narrow pores (r(Tfs) greater than or equal to 10r(pore), and possibly more). Each such vesicle then behaves as a responsive, self-optimizing, nanorobotic transport device. The mixed micelles with identical components or the simple vesicles (liposomes) with a similar size as that of unusually deformable vesicles do not share this quality. Liposomes only traverse barriers when r(lipos) less than or equal to 1.5r(pore); they clog narrower pores, unless they get fragmented in/before the orifice. Mammalian skin is perforated by a very large number (greater than or equal to10(7) cm(-2)) of very narrow (r(pore) similar to 0.3 nm) intercellular hydrophilic pores. These can be widened into the barrier-spanning, hydrophilic transcutaneous pathways (r(pathway) similar to 20-30 nm) by ultradeformable vesicles. Mixed micelles or liposomes do not activate such pores because they are respectively too small or too undeformable (kappa(lipos), > 10kappa(Tfs)) and large (2r(lipos)/nm greater than or equal to 45 much greater than 20) for the purpose. The outer two-thirds of the skin barrier also contain fewer but wider openings (r(pore) greater than or equal to 3 mum), which encircle groups of cells in the stratum corneum. The resulting sparse, low-resistance intercluster pathway can accommodate various sufficiently small aggregates (r(a) less than or equal to 2 mum), including liposomes and micelles. All the tested lipidic particles can, therefore, reach locally similar to60% of the skin barrier depth, on the average. Ultradeformable vesicles move through the skin most uniformly and to the greatest relative depth, however. Locally or near the skin surface the distribution of different lipid aggregates that penetrate a barrier can be similar.