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

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.

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.

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 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.

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.