Cell-Penetrating Peptides Could Make Protein Drugs Available as Nose Sprays and Oral Films | Research

The takeaway

This review examines how cell-penetrating peptides can enhance protein and peptide delivery across nasal, buccal, sublingual, and oral mucosal barriers, addressing the structural challenges of each route for non-invasive drug delivery.

4 mucosal routes, distinct barriers
Nasal, buccal, sublingual, and oral mucosa each present unique challenges for CPP-mediated protein delivery, requiring route-specific optimization

What the researchers found

CPPs are a versatile platform for enhancing protein permeation across multiple mucosal barriers, with route-specific optimization needed to address the distinct structural and physicochemical challenges of nasal, buccal, sublingual, and oral mucosa.

Why it matters

Eliminating the need for injections would transform how protein drugs are delivered — improving patient comfort, compliance, and accessibility. CPPs represent one of the most promising approaches to achieve this, and understanding which routes work best for which drugs is critical for advancing the technology.

The numbers in context

Review covers four mucosal routes (nasal, buccal, sublingual, oral) and their distinct barrier properties affecting CPP-mediated delivery.

How the study worked

Comprehensive review examining the structural and physicochemical attributes of nasal, buccal, sublingual, and oral mucosal barriers, recent CPP development for protein delivery across each barrier, and challenges for clinical translation.

Who was studied

Literature review of CPP-mediated mucosal delivery

What this study cannot tell us

Review article — no new experimental data. CPP-mediated delivery faces significant challenges including peptide stability, formulation complexity, dose variability, and the gap between in vitro and in vivo performance. Regulatory pathways for CPP-drug conjugates are still undefined. Safety concerns about chronic mucosal exposure to CPPs are not fully resolved.

How to read the evidence

Moderate evidence as a comprehensive review synthesizing the current state of CPP-mediated transmucosal delivery. Individual studies cited range from in vitro to limited in vivo preclinical data.

When this study was published

Published in 2024, reflecting the current state of a field that has advanced significantly with improved CPP designs and formulation technologies.

The bigger picture

The protein therapeutics market exceeds $300 billion, but nearly all protein drugs require injection. Non-invasive alternatives have been a pharmaceutical holy grail for decades. CPPs address the fundamental problem — getting large molecules across biological barriers — in a modular way that can be adapted to different drugs and delivery routes. Success here would impact millions of patients who currently need regular injections.

Questions still open

Which mucosal route will prove most practical for CPP-mediated protein delivery in clinical practice?
Can CPP-drug formulations achieve reproducible dosing comparable to injectable protein therapeutics?
What is the long-term safety profile of repeated mucosal exposure to cell-penetrating peptides?

Common questions

Why can't protein drugs like insulin just be taken as pills?

Proteins face three major barriers when taken orally: (1) stomach acid and digestive enzymes destroy them, (2) they're too large to passively cross the intestinal wall, and (3) even if absorbed, the liver metabolizes most of them before they reach the bloodstream (first-pass effect). Cell-penetrating peptides address barrier #2 by actively ferrying the drug molecules across the gut wall, but you still need to solve problems #1 and #3 — which is why nasal and sublingual routes (which bypass the stomach and liver) are also being explored.

What is a cell-penetrating peptide?

CPPs are short amino acid sequences (typically 5-30 amino acids) that have the remarkable ability to cross cell membranes and carry other molecules with them. They were discovered by observing how certain viral proteins can enter cells. When attached to or mixed with protein drugs, CPPs can facilitate their transport across mucosal barriers — essentially acting as molecular escorts that get the drug past biological security checkpoints.

Read the original research

Cell-penetrating peptides for transmucosal delivery of proteins.

Journal of controlled release : official journal of the Controlled Release Society, 366, 864-878

View on PubMed ↗Publisher’s paper ↗

Citation

Wu, Jiamin; Roesger, Sophie; Jones, Natalie; Hu, Che-Ming J; Li, Shyh-Dar. (2024). Cell-penetrating peptides for transmucosal delivery of proteins.. Journal of controlled release : official journal of the Controlled Release Society, 366, 864-878. https://doi.org/10.1016/j.jconrel.2024.01.038