Designing Influenza Virus-derived Cell-penetrating Peptides for Antigen Delivery: Integrating Uptake Efficiency, Safety, and Receptor Targeting
Sanaz Sadeh, Amir Ghaemi, Nazila Arbab Soleimani, Majid Moghbeli, Golnaz BahramAli
Abstract
Successful antigen delivery is of paramount importance for successful vaccination. Cell-penetrating peptides (CPPs) offer a highly effective means of delivering antigens, nucleic acids, and other drug compounds to cells. However, their mechanisms of action remain poorly understood and require further investigation. This study sought to identify novel CPPs within the influenza virus proteome using computational screening methods for vaccine and antigen delivery. CPP candidates were screened from major influenza proteins using CellPPD, C2Pred, and PreTP-EL.
Introduction
The development of vaccines is a major step toward the elimination of various diseases. Successful vaccination depends on long-lasting immune responses and protection against infections. This technique requires an accurate and effective antigen delivery to stimulate the immune system. Different methods are used to transport cargo across barriers.
CPPs, also known as protein transduction domains (PTDs) or Trojan peptides, are powerful biological nanocarriers that can overcome natural barriers. They can cross biological membranes and deliver membrane-impermeable compounds into the cells.
Materials and Methods:
This study aimed to identify and describe Influenza A virus protein-derived cell-penetrating peptides (CPPs) using a combination of bioinformatics tools to screen the influenza A virus (H1N1 subtype) proteome for CPP and non-CPP candidates. This study was performed entirely using in-silico analyses and did not involve human participants, animal subjects, or biological specimens. Therefore, no ethics approval or consent was required.
Discussion
Successful vaccine development remains a top priority because of the inefficiency of immunization mechanisms against most viruses. Therefore, it is important to enhance intracellular antigen delivery systems, particularly for second-generation subunit and mRNA vaccines. Cell-penetrating peptides (CPPs) are potentially powerful non-viral vectors with low immunogenicity, scalability, and safety that can transport proteins, nucleic acids, and antigens directly into antigen-presenting cells (APCs), thereby supporting enhanced antigen presentation and strong immune responses.
Citation: Sadeh S, Ghaemi A, Soleimani NA, Moghbeli M, BahramAli G (2025) Designing influenza virus-derived cell-penetrating peptides for antigen delivery: Integrating uptake efficiency, safety, and receptor targeting. PLoS One 20(12): e0338028. https://doi.org/10.1371/journal.pone.0338028
Editor: Salman Sadullah Usmani, Albert Einstein College of Medicine, UNITED STATES OF AMERICA
Received: March 2, 2025; Accepted: November 17, 2025; Published: December 9, 2025.
Copyright: © 2025 Sadeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by Pasteur Institute of Iran (Grant ID; 2282) to Amir Ghaemi. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors declare they have no conflict of interest.
