The one-bead, one-compound (OBOC) combinatorial library technology was created in 1990 in Tucson during my first year as an Assistant Professor at the University of Arizona. This technology enables the synthesis of millions of peptides, peptidomimetics, or small molecules on solid-phase beads, with each bead displaying multiple copies of a single compound. Over the past 36 years, OBOC technology has served as a powerful discovery platform for identifying cancer-targeting peptides, enzyme substrates and inhibitors, antifungal peptides, membrane-active peptides, cell-penetrating peptides, self-assembling peptides, stealth peptides, SARS-CoV-2 spike protein binding peptides, and death ligands. Using a proximity-driven covalent screening strategy, we further developed reactive affinity elements (RAEs) that enable site-specific modification of human serum albumin, an excellent endogenous carrier for drug delivery.
Building on these discoveries, we developed a versatile peptide-based, receptor-mediated transformable nanoplatform (TNP) for cancer therapy. TNP is composed of peptide monomers containing three functional domains: a cancer-targeting peptide, a β-sheet-forming peptide segment, and a hydrophobic moiety. In aqueous solution, these monomers self-assemble into micellar nanoparticles that undergo receptor-triggered transformation into nanofibrillar networks within the tumor microenvironment (TME). This unique property enables selective accumulation and prolonged retention in tumors. We have successfully applied the TNP platform to phototherapy, immunotherapy, and drug delivery in multiple tumor models. Taking advantage of the extended retention of the nanofibrillar network in the TME, we further developed a two-component therapeutic strategy in which TNP acts as a pre-targeting agent and a methyl-tetrazine–containing prodrug serves as the second component for in vivo bio-orthogonal click ligation. This approach produced excellent tumor responses in preclinical models.