2022
DOI: 10.1021/jacs.2c07420
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Hydroxyl-Rich Hydrophilic Endocytosis-Promoting Peptide with No Positive Charge

Abstract: Delivering cargo molecules across the plasma membrane is critical for biomedical research, and the need to develop molecularly well-defined tags that enable cargo transportation is ever-increasing. We report here a hydrophilic endocytosis-promoting peptide (EPP6) rich in hydroxyl groups with no positive charge. EPP6 can transport a wide array of small-molecule cargos into a diverse panel of animal cells. Mechanistic studies revealed that it entered the cells through a caveolin- and dynamin-dependent endocytosi… Show more

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Cited by 15 publications
(6 citation statements)
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References 46 publications
(109 reference statements)
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“…While mechanistic details are still debated, the majority of CPPs enter cells via endocytosis. Although recent reports have described uncharged sequences, [2] most CPPs are either polycationic or amphipathic. Noncanonical modifications, such as d ‐amino acids, unnatural side chains and macrocyclization are known to improve cellular uptake and overall stability [3]…”
Section: Figurementioning
confidence: 99%
“…While mechanistic details are still debated, the majority of CPPs enter cells via endocytosis. Although recent reports have described uncharged sequences, [2] most CPPs are either polycationic or amphipathic. Noncanonical modifications, such as d ‐amino acids, unnatural side chains and macrocyclization are known to improve cellular uptake and overall stability [3]…”
Section: Figurementioning
confidence: 99%
“…Different nanoplatforms based on phosphorus dendrimers have been created as carriers for the delivery of genes or drugs due to their biological activities. The interaction of cationic phosphorus dendrimers with proteins has been described, while the necessity of depending on positive charge to deliver protein intracellularly needs to be reevaluated given that high densities of positive charge cause unpredictable cytotoxicity . Therefore, it is vital to develop efficient carriers based on anionic phosphorus dendrimers to effectively deliver functional proteins to exert synergistic and enhanced therapeutic effects.…”
Section: Introductionmentioning
confidence: 99%
“…Internalization of particles with a maximum diameter of 100–200 nm is commonly achieved via receptor-mediated endocytosis . Cell-penetrating peptides (CPPs), short peptides capable of transporting diverse substances into cells, including small molecules, nanoparticles, genes, and proteins, have gained attention for their efficient transduction mechanisms. Despite their high transduction efficiency and minimal cell damage, CPPs lack specificity, limiting their applicability in drug delivery. Addressing this issue, researchers have linked CPPs with anions to prevent nonspecific cell membrane penetration and undesired molecular interactions. , In the acidic tumor microenvironment or within cancer cell endosomes/lysosomes, the associated anion is shed, activating the CPP function. , TAT peptide, originating from the human immunodeficiency virus type 1 (HIV-1) TAT protein transduction domain, possesses a robust ability to penetrate various cell membranes. , However, the inherent positively charged property of TAT makes it prone to binding with blood proteins, leading to rapid clearance from blood circulation. To circumvent this issue, poly­(ethylene glycol) (PEG) molecules are utilized to create a hydrophilic coating that masks the positive charge of TAT. Under low pH conditions, this coating is removed, facilitating the effective internalization of TAT-conjugated nanomaterials by tumor cells. , Succinyl chloride was reported to participate in the amidation of the lysine residue in TAT. , At neutral pH, the amide bond impedes penetration of the positively charged TAT through the cell membrane.…”
Section: Introductionmentioning
confidence: 99%