Peptide-based strategies for enhanced cell uptake, transcellular transport, and circulation: Mechanisms and challenges

Peptides are emerging as a new tool in drug and gene delivery. Peptide-drug conjugates and peptide-modified drug delivery systems provide new opportunities to avoid macrophage recognition and subsequent phagocytosis, cross endothelial and epithelial barriers, and enter the cytoplasm of target cells. Peptides are relatively small, low-cost, and are stable in a wide range of biological conditions. In this review, we summarize recent work in designing peptides to enhance penetration of biological barriers, increase cell uptake, and avoid the immune system. We highlight recent successes and contradictory results, and outline common emerging concepts and design rules. The development of sequence-structure–function relationships and standard protocols for benchmarking will be a key to progress in the field.