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Review
. 2023 Jul 12;11(7):1971.
doi: 10.3390/biomedicines11071971.

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

Zhe Sun  1 , Jinhai Huang  1 , Zvi Fishelson  2 , Chenhui Wang  3 , Sihe Zhang  3
Affiliations
Review

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

Zhe Sun et al. Biomedicines. .

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, improved targeting efficiency and stimuli-responsive design 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.

Keywords: biological barrier; cell-penetrating peptide; cellular uptake mechanism; macromolecular drug delivery; optimized strategy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Delivery systems for macromolecular drugs.
Figure 2
Figure 2
Milestones for the discovery and development of CPPs.
Figure 3
Figure 3
The components and classification of the CPP-based macromolecular drug delivery.
Figure 4
Figure 4
Cellular uptake mechanisms of CPP-based macromolecular drug delivery. The mechanisms mainly include two categories: direct penetration pathways and endocytotic pathways. Direct penetration pathways are usually energy-independent, whereas endocytotic pathways are energy-dependent. In order for the CPP-cargos to function after entering the target cells, proteins and RNA endosomes must escape into the cytoplasm, whereas pDNA must enter the nucleus.
Figure 5
Figure 5
Biological barriers to CPP-based delivery systems. Biological barriers include tissue pressure, opsonization, rapid kidney filtration, serum endonucleases, a macrophage system, and hemorheological limitations. After the delivered macromolecular drugs enter the target cells, the biological barriers mainly include the encapsulation of endosomal vesicles, lysosome degradation, and the difficulty in intracellular transmission. The delivery system loaded with pDNA must enter the nucleus to function; thus, the NPC is another barrier to the pDNA delivery system.
Figure 6
Figure 6
The main stimuli-responsive strategies of CPP-based macromolecular drug delivery. This figure lists the main stimulus factors used in stimuli-responsive strategies of CPP-based delivery systems in recent years, including pH, enzyme, light, ultrasound, ROS, ATP, and redox.
Figure 7
Figure 7
Conditions for successful CPP-based macromolecular drug delivery. In the experimental phase of the delivery system, safety and efficiency are the main concerns. In the final application to the clinic, manufacturing and cost will be essential factors to be considered. Successful CPP-based delivery of macromolecular drugs must concomitantly satisfy the conditions of safety, efficiency, manufacturing, and cost.
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