1. National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR. China.
2. Department of Tumor and Immunology in precision medical institute, Western China Science and Technology Innovation Port, Xi'an, 710004, PR. China.
3. Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR. China.
4. Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
5. Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR. China.
6. Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 710003, PR. China.
7. The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR. China.
*These authors contributed equally to this work.
Peptide-derived nanocomposites have been exhibiting fascinating biological advantages, including but not limited to excellent biocompatibility, biological degradation, high targetability and subsequent potent therapeutic efficacy. While some successes have been achieved in the nanoengineering of peptide-based architectures with defined dimensions and medical functions, enormous challenges remain about clinical nano-pharmaceutics of peptides, especially those modulating intracellular protein-protein interactions (PPIs).
Methods: We developed a general method to translate intracellular-PPI-targeted peptides into a bioavailable peptide-auric spheroidal nanohybrid (SNH), for which polymeric peptide-Auric precursors [Au1+-S-peptide]n are in-situ reduced on the surface of gold nanoseeds via a simple and mild reaction. As proofs of concept, three cytomembrane-impenetrable peptides with different physicochemical properties were successfully engineered into stable and tumor-specific SNH respectively.
Results: To highlight the advantage of SNH, PMI, a hydrophobic and enzyme-intolerant peptide capable of p53 restoration, was selected to challenge the power of SNH in a colon tumor xenografts model. PMI-Au SNH in vivo suppressed tumor growth potently after three administrations: intravenous injection, intraperitoneal injection and gastric perfusion, and maintained a favorable therapeutic safety.
Conclusion: This therapeutically feasible strategy of peptide nanoengineering will allow us to fabricate a series of nanomedicines to modulate carcinogenic PPIs that hide and multiply inside cells, and in all likelihood reinvigorate the development of peptide drug against wide varieties of human diseases.
Keywords: peptide, nanoparticle, anti-cancer, peptide therapeutics, protein-protein interactions