Intracellular Transport of Monomeric Peptides, (Poly)Peptide-Based Coacervates and Fibrils: Mechanisms and Prospects for Drug Delivery.

Peptides are emerging as versatile platforms in medicine, serving as therapeutic agents, diagnostic probes, and drug delivery vehicles. Their physical state-in a form of monomeric cell-penetrating peptides (CPPs), liquid-like coacervates, or solid amyloid fibrils-critically determines their interaction with cell surfaces and subsequent intracellular trafficking pathways. While the transport of CPPs has been extensively studied, the mechanisms governing the cellular uptake of peptide-based coacervates and fibrils are less understood. This review summarizes the current understanding of the intracellular transport mechanisms of all three distinct peptide states and their complexes or conjugates with cargo molecules. We examine a range of pathways, including direct membrane translocation, several endocytosis subtypes, and phagocytosis-like transport. Particular attention is given to unique aspects observed exclusively for CPPs, coacervates, or fibrils. Further verification and detailed characterization of internalization mechanisms are crucial for the rational design of next-generation peptide-based carriers that allow for precise cargo delivery and therapeutic efficacy.