RT Journal Article SR Electronic T1 Temperature- and rigidity-mediated rapid transport of lipid nanovesicles in hydrogels JF Proceedings of the National Academy of Sciences JO Proc Natl Acad Sci USA FD National Academy of Sciences SP 5362 OP 5369 DO 10.1073/pnas.1818924116 VO 116 IS 12 A1 Yu, Miaorong A1 Song, Wenyi A1 Tian, Falin A1 Dai, Zhuo A1 Zhu, Quanlei A1 Ahmad, Ejaj A1 Guo, Shiyan A1 Zhu, Chunliu A1 Zhong, Haijun A1 Yuan, Yongchun A1 Zhang, Tao A1 Yi, Xin A1 Shi, Xinghua A1 Gan, Yong A1 Gao, Huajian YR 2019 UL //www.hmclip.net/content/116/12/5362.abstract AB Lipid vesicles such as liposomes are widely present in biological systems and drug delivery applications. Numerous studies have focused on their roles in intercellular communication, signaling, and trafficking. Little is known, however, about the correlation between temperature and transport rate of these vesicles in biological media. Here, we report a temperature- and rigidity-mediated rapid transport mechanism by which liposomes attain optimal diffusivity near a phase transition temperature. Remarkably, liposomes with phase transition temperature around the body temperature are observed to overcome multiple biological barriers and show substantial improvement in drug delivery efficacy.Lipid nanovesicles are widely present as transport vehicles in living organisms and can serve as efficient drug delivery vectors. It is known that the size and surface charge of nanovesicles can affect their diffusion behaviors in biological hydrogels such as mucus. However, how temperature effects, including those of both ambient temperature and phase transition temperature (Tm), influence vehicle transport across various biological barriers outside and inside the cell remains unclear. Here, we utilize a series of liposomes with different Tm as typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when their Tm is around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes with Tm around body temperature (i.e., ～37 °C) exhibit enhanced cellular uptake in mucus-secreting epithelium and show significant improvement in oral insulin delivery efficacy in diabetic rats compared with those with higher or lower Tm. Molecular-dynamics (MD) simulations and superresolution microscopy reveal a temperature- and rigidity-mediated rapid transport mechanism in which the liposomes frequently deform into an ellipsoidal shape near the phase transition temperature during diffusion in biological hydrogels. These findings enhance our understanding of the effect of temperature and rigidity on extracellular and intracellular functions of nanovesicles such as endosomes, exosomes, and argosomes, and suggest that matching Tm to ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors.