Nanoparticles with Cell-Penetrating Peptides for Oral Delivery: A Case for Oral Delivery of Insulin.

The expanding protein-based drug market is facing limitations from invasive delivery methods. These methods can cause discomfort and pose infection risk, particularly for the chronic disease patients such as diabetes requiring insulin with adherence challenges. Oral insulin, though preferred, suffers from <2% bioavailability, thus, nano-drug delivery system (NDDS) is becoming a highly promising strategy to enhance bioavailability and stability. However, the low expression of receptors and limited uptake capacity remain challenge. The use of cell-penetrating peptides (CPPs) will enhance the permeability of epithelial cells, and combining them with nanoparticles (NPs) can further improve the stability of protein-based drugs in blood circulation and facilitate the development of efficient delivery carriers. This comprehensive review delves into the design, synthesis, classification, challenges, and cellular uptake mechanisms of CPPs-cargo complexes and CPPs-NP nanocarriers for insulin delivery. Furthermore, it provides an in-depth exploration of the challenges and prospects of these innovative approaches.