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1. How Cargo Identity Alters the Uptake of Cell-Penetrating Peptide (CPP)/Cargo Complexes: A Study on the Effect of Net Cargo Charge and Length

   https://doi.org/10.3390/cells11071195  

   H.C. Hymel, A. Rahnama ( April 2022 , Cells)
2. A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action

   https://doi.org/10.1016/j.jconrel.2020.05.030  

   Komin, Alexander ; Bogorad, Maxim I. ; Lin, Ran ; Cui, Honggang ; Searson, Peter C. ; Hristova, Kalina ( August 2020 , Journal of Controlled Release)

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3. Leveraging Swelling Polymer Nanoparticle Reversibility for Cargo Loading

   https://doi.org/10.1021/acsanm.4c00571  

   Tuga, Beza ; Ligocki, Andrea T. ; Haynes, Christy L. ( March 2024 , ACS Applied Nano Materials)

   pH-responsive polymeric nanoparticles are an exciting class of stimuli-responsive materials that can respond to changes in pH and, as a result, have been developed for numerous applications in biomedicine, such as the loading and delivery of various cargoes. One common transformation is nanoparticle swelling due to the protonation or deprotonation of specific side chain moieties in the polymer structure. When the pH trigger is removed, the swelling can be reversed, and this process can be continually cycled by adjusting the pH. In this work, we are leveraging this swelling–deswelling–reswelling mechanism to develop a simple, fast, and easy loading strategy for a class of cross-linked polymeric nanoparticles, poly-2-(diethylamino) ethyl methacrylate (pDEAEMA), that can reversibly swell below pH 7.3, and a dye, rhodamine B isothiocyanate (RITC), as a proof-of-concept cargo molecule while comparing to poly(methyl methacrylate) (pMMA) nanoparticles as a nonswelling control. A free radical polymerization was used to generate pDEAEMA nanoparticles at three different sizes by varying the synthesis temperature. Their pH-dependent swelling and deswelling were extensively characterized using dynamic light scattering and transmission electron microscopy, which revealed a reversible increase in size for pDEAEMA nanoparticles in acidic media, whereas pMMA nanoparticles remain constant. Following dye loading, pDEAEMA nanoparticles show significant fluorescence intensity when compared to pMMA nanoparticles, suggesting that the reversible swelling is key for successful loading. Upon acidic treatment, there is a significant decrease in the fluorescence intensity when compared to the dye-loaded nanoparticles in basic media, which could be due to dilution of the dye when released in the acidic medium solution. Interestingly, nanoparticle size had no impact on dye loading properties, suggesting that the dye molecules only go so far into the polymer nanoparticle. Additionally, confocal microscopy images reveal pDEAEMA nanoparticles with higher RITC fluorescence intensity in acidic media but a lower RITC fluorescence intensity in basic media, while pMMA nanoparticles show no differences. Together, these results showcase a size reversibility-driven cargo loading mechanism that has the potential to be applied to other beneficial cargoes and for various applications. 

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4. Image-based measurement of cargo traffic flow in complex neurite networks

   https://doi.org/10.1109/ICIP.2017.8296891  

   Chai, Xiaoqi ; Qian, Douglas ; Ba, Qinle ; Li, Angran ; Zhang, Yongjie Jessica ; Yang, Ge ( September 2017 , IEEE International Conference on Image Processing)
5. Allosterically coupled conformational dynamics in solution prepare the sterol transfer protein StarD4 to release its cargo upon interaction with target membranes

   https://doi.org/10.3389/fmolb.2023.1197154  

   Xie, Hengyi ; Weinstein, Harel ( May 2023 , Frontiers in Molecular Biosciences)

   Complex mechanisms regulate the cellular distribution of cholesterol, a critical component of eukaryote membranes involved in regulation of membrane protein functions directly and through the physiochemical properties of membranes. StarD4, a member of the steroidogenic acute regulator-related lipid-transfer (StART) domain (StARD)-containing protein family, is a highly efficient sterol-specific transfer protein involved in cholesterol homeostasis. Its mechanism of cargo loading and release remains unknown despite recent insights into the key role of phosphatidylinositol phosphates in modulating its interactions with target membranes. We have used large-scale atomistic Molecular dynamics (MD) simulations to study how the dynamics of cholesterol bound to the StarD4 protein can affect interaction with target membranes, and cargo delivery. We identify the two major cholesterol (CHL) binding modes in the hydrophobic pocket of StarD4, one near S136&S147 (the Ser-mode), and another closer to the putative release gate located near W171, R92&Y117 (the Trp-mode). We show that conformational changes of StarD4 associated directly with the transition between these binding modes facilitate the opening of the gate. To understand the dynamics of this connection we apply a machine-learning algorithm for the detection of rare events in MD trajectories (RED), which reveals the structural motifs involved in the opening of a front gate and a back corridor in the StarD4 structure occurring together with the spontaneous transition of CHL from the Ser-mode of binding to the Trp-mode. Further analysis of MD trajectory data with the information-theory based NbIT method reveals the allosteric network connecting the CHL binding site to the functionally important structural components of the gate and corridor. Mutations of residues in the allosteric network are shown to affect the performance of the allosteric connection. These findings outline an allosteric mechanism which prepares the CHL-bound StarD4 to release and deliver the cargo when it is bound to the target membrane.

    

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