Prenylated Chemically Self-Assembled Nanorings: A Versatile Platform for Macro-Chemical Biology

Abstract

Macro-chemical biology uses chemical methods and biomacromolecules to study and manipulate biological systems at the cellular level, and biomacromolecules capable of manipulating cell fates have been demonstrated exceedingly valuable for assorted fundamental research and therapeutic applications. Protein conjugates, as a type of chemically engineered hybrid macromolecules, are synthesized through conjugations of proteins with functional molecules of diverse types and have been exploited to manipulate cell functions in various aspects, including regulation of intercellular interactions, intervention in intracellular biological pathways, and termination of cell proliferation. Although effective in numerous pre-clinical studies, the clinical translation of therapeutic protein conjugates remains challenging and hindered by some limitations, which in turn underlines some ideal features for designing clinically desirable protein conjugates. Hence, to meet these challenges, our group has constructed a versatile macromolecular platform with self-assembling protein-lipid conjugates, namely, prenylated chemically self-assembled nanorings (CSANs), for macro-chemical biology studies. This multivalent system has exhibited exceptional stability, function reversibility, target cell selectivity, and broad utility, and was shown to effectively regulate cell fates for multiple biomedical applications. We first used the prenylated CSANs as a universal non-genetic system to stably modify cell surface and demonstrated they can mediate reversible cell-cell interactions for fundamental research and adoptive cell therapy. Thereafter, we discovered the CSANs can specifically transfer from the CSAN-modified cell to the target cell during cell-cell interactions, and such intercellular CSAN transfer is dependent on specific ligand-receptor engagement. Therefore, with fluorescent dyes conjugated to the farnesylated CSANs through click reactions, the CSAN assisted cell-cell cargo transfer (C4T) was utilized as a tool to record cell-cell interactions. Furthermore, by conjugating functional oligonucleotides and cancer drugs to the farnesylated CSANs, we were able to manipulate cell functions by the C4T approach. Finally, the cancer drug MMAE was conjugated to the CSANs to form a targeted drugdelivery system for the treatment of EGFR-positive cancer. The MMAE-loaded anti-EGFR CSANs manifested notable cytotoxicity and selectivity against EGFR-positive cancer cells and were also found to provoke immunogenic death of the cancer cells. Altogether, these promising results demonstrate that the prenylated CSANs are a versatile platform applicable to a variety of fundamental research and therapeutic purposes.