Cell-Penetrating Peptide-Based Delivery of Macromolecular Drugs: Development, Strategies, and Progress

Abstract

Cell-penetrating peptides (CPPs), developed for more than 30 years, are still being extensively studied due to their excellent delivery performance. Compared with other delivery vehicles, CPPs hold promise for delivering different types of drugs. Here, we review the development process of CPPs and summarize the composition and classification of the CPP-based delivery systems, cellular uptake mechanisms, influencing factors, and biological barriers. We also summarize the optimization routes of CPP-based macromolecular drug delivery from stability and targeting perspectives. Strategies for enhanced endosomal escape, which prolong its half-life in blood, improve targeting efficiency and stimuli-responsive design and are comprehensively summarized for CPP-based macromolecule delivery. Finally, after concluding the clinical trials of CPP-based drug delivery systems, we extracted the necessary conditions for a successful CPP-based delivery system. This review provides the latest framework for the CPP-based delivery of macromolecular drugs and summarizes the optimized strategies to improve delivery efficiency.

A Nucleus-Targeting WT1 Antagonistic Peptide Encapsulated in Polymeric Nanomicelles Combats Refractory Chronic Myeloid Leukemia

“…Nanoparticles exceeding 6 nm in diameter are often processed by the liver and spleen, while those smaller than 6 nm are processed by the kidneys [ 58 ]. In addition, if nanoparticles are smaller than 10 nm, they are quickly cleared by the kidneys and do not easily accumulate at the tumor site through EPR effect [ 60 ]. In our study, M—WIP2W, approximately 20 nm in size, showed promise with regard to efficient distribution in the body.…”

Nature-inspired peptide of MtDef4 C-terminus tail enables protein delivery in mammalian cells

“…Typically, most short CPPs are recognized by their positive charge, allowing them to traverse the cell membrane at relatively low concentrations. Although several clinical trials involving conjugated CPPs are ongoing, no CPP-based drug has been approved 40 , 41 . Consequently, the discovery and design of novel CPPs with improved efficiency, specificity, and safety profiles remain highly desirable in biomedical research.…”

Porous protein crystals: synthesis and applications

“…119 An additional justification for these mutations was based on ample evidence that uptake and endosomal escape are heavily dependent on the presence of numerous positively charged residues, such as lysine and arginine. [120][121][122][123][124][125] Independent staining of endosomes and crystals revealed that while cellular uptake occurred for both versions of Cry3Aa, endosomal escape into the cytoplasm was only observed for Pos3Aa crystals. Using different endocytic inhibitors, it was further observed that uptake was not receptor mediated, but instead occurred via macropinocytosis.…”