To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.

Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules (i.e., the acyl chain length and saturation) are known to affect the mechanical properties of SUVs and consequently regulate their biological behaviors and functions, the underlying mechanism remains elusive. Here, we combined theoretical modeling and experimental investigation to probe the mechanical behaviors of SUVs with different lipid compositions. The membrane bending rigidity of SUVs increased with increasing chain length and saturation, resulting in differences in the vesicle rigidity and deformable capacity. Furthermore, we tested the tumor delivery capacity of liposomes with low, intermediate, and high rigidity as typical models for SUVs. Interestingly, liposomes with intermediate rigidity exhibited better tumor extracellular matrix diffusion and multicellular spheroid (MCS) penetration and retention than that of their stiffer or softer counterparts, contributing to improved tumor suppression. Stiff SUVs had superior cellular internalization capacity but intermediate tumor delivery efficacy. Stimulated emission depletion microscopy directly showed that the optimal formulation was able to transform to a rod-like shape in MCSs, which stimulated fast transport in tumor tissues. In contrast, stiff liposomes hardly deformed, whereas soft liposomes changed their shape irregularly, which slowed their MCS penetration. Our findings introduce special perspectives from which to map the detailed mechanical properties of SUVs with different compositions, provide clues for understanding the biological functions of SUVs, and suggest that liposome mechanics may be a design parameter for enhancing drug delivery.

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 differentTmas typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when theirTmis around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes withTmaround 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 lowerTm. 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 matchingTmto ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors.

In this work we perform large scale dissipative particle dynamics (DPD) simulations to study the interaction between nanoparticles (NPs) and vesicles, and discuss their potential implications for NP-cell interactions. First, we determine the different pathways of NP internalization and their dependence on NP size, NP concentration, vesicle excess area, and NP-vesicle attraction. In particular, we identify three pathways for spontaneous NP penetration, which are here called the cooperative chain-like penetration, direct penetration and inverted micelle-like penetration, and investigate how different factors affect the penetration processes. Then, we demonstrate that adsorption of NPs often induces NP clustering on the outer and/or inner surfaces of vesicles, leading to different vesicle responses, including the change of vesicle morphology, formation of protuberance, and vesicle rupture.

We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable −NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment.

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The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3–containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3–containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)–, transient receptor potential cation channel subfamily V member 1 (TRPV1)–, or tyrosine hydroxylase (TH)–positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3–containing K2P channels as a druggable target for treating pain.

Infections by the Ebola virus (EBOV) rapidly cause fatal hemorrhagic fever in humans. Viral entry into host cells is the most critical step in infection and an attractive target for therapeutic intervention. Herein, the invagination behavior and entry dynamics of filamentous Ebola virus-like particles (EBO-VLPs) were investigated using a force tracing technique based on atomic force microscopy and single-particle fluorescence tracking in real time. The filamentous EBOV-VLPs might enter cells in both horizontal and vertical modes, and the virus–receptor interactions during endocytic uptake were analyzed. In addition, molecular dynamics simulations and engulfment energy analysis further depicted EBO-VLP entry in the horizontal and vertical directions and suggested that internalization in the vertical direction requires a larger force and more time. This report provides useful information for further revealing the mechanism of viral infection, which is important for understanding viral pathogenesis.