Self‐Assembling Proteins for Design of Anticancer Nanodrugs

Abstract

Inspired by the diverse protein-based structures and materials in organisms, proteins have been expected as promising biological components for constructing nanomaterials toward various applications. In numerous studies protein-based nanomaterials have been constructed with the merits of abundant bioactivity and good biocompatibility. However, self-assembly of proteins as a dominant approach in constructing anticancer nanodrugs has not been reviewed.Here, we provide a comprehensive account of the role of protein self-assembly in fabrication, regulation, and application of anticancer nanodrugs. The supramolecular strategies, building blocks, and molecular interactions of protein selfassembly as well as the properties, functions, and applica-tions of the resulting nanodrugs are discussed. The applications in chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, gene therapy, and combination therapy are included. Especially, manipulation of molecular interactions for realizing cancer-specific response and cancer theranostics are emphasized. By expounding the impact of molecular interactions on therapeutic activity, rational design of highly efficient protein-based nanodrugs for precision anticancer therapy can be envisioned. Also, the challenges and perspectives in constructing nanodrugs based on protein self-assembly are presented to advance clinical translation of protein-based nanodrugs and next-generation nanomedicine. 2 3 4 5 6 7 8

Metal‐Coordinated Supramolecular Self‐Assemblies for Cancer Theranostics

“…Ru complexes have drawn increasing attention as photosensitizers because their photochemical and biological properties can be adjusted with an appropriate choice of ligands for PDT. [ 2a ] For example, Song et al. prepared a dual NIR‐II PA and FL imaging vesicle nanoplatform by the self‐assembly of amphiphilic gold nanorod (AuNR) coated with a light‐responsive polyprodrug comprising a Ru complex (PolyRu) constructed via coordination bonds with the cyano groups of poly(6‐(4‐cyanophenoxy) hexyl methacrylate, a Ru complex [Ru(tpy)(biq)](PF 6 ) 2 , PEG, and NIR‐II IR 1061 dye.…”

“…[ 1 ] An appropriately designed nanoplatform that combines a variety of functional components is required for effective theranostics. [ 2 ] Presently, the most important requirement of the developed nanomedicines for bio‐applications is biosafety; however, the relatively high toxicity and low biodegradability of the majority of nanomedicines have greatly restricted their clinical translation. [ 3 ] Moreover, solid tumor theranostic nanomedicines face the very intractable problem of low accumulation in tumors.…”

“…Metal coordination is used to adjust the self‐assembly routes and to tailor the morphologies of the resulting supramolecular architectures. [ 2 , 10 ] The metal ions, along with the binding ligands, determine the properties of the metal‐coordinated supramolecule because various coordination metal ions differ in size, binding affinity, coordination geometry, coordination number, and charge density. [ 10 , 12 ] As an example, the small and dense hydration spheres of Mg 2+ ions are not conducive to ligand coordination, whereas the flexible coordination geometry and unoccupied higher‐energy orbitals of Zn 2+ ions lead to octahedral and tetrahedral architectures.…”

“…[ 10 , 12 ] As an example, the small and dense hydration spheres of Mg 2+ ions are not conducive to ligand coordination, whereas the flexible coordination geometry and unoccupied higher‐energy orbitals of Zn 2+ ions lead to octahedral and tetrahedral architectures. [ 2 , 13 ] Because different metal ions are involved in coordination, the metal–ligand binding affinity, the number of binding ligands, and the orientation of the coordination bond also undergo changes, which facilitates the formation of nanostructures with ideal dimensions, morphology, and physicochemical properties. [ 14 ] Numerous studies have demonstrated that metal coordination has a significant influence on guiding the self‐assembly of organic ligands into nanomaterials.…”

Breaking the Iron Homeostasis: A “Trojan Horse” Self-Assembled Nanodrug Sensitizes Homologous Recombination Proficient Ovarian Cancer Cells to PARP Inhibition

“…During this process, GA served as a ligand to react with Ga 3+ to form a stable metal–organic coordination nanoformulation. It has also been reported that GA could exhibit certain antitumor activities. , Finally, olaparib, a universal PARP inhibitor, was incorporated into the BSA-Ga 3+ complex via the hydrophobic effect to form the olaparib-Ga nanodrug through self-assembly. − The anticancer effects of the olaparib-Ga nanodrug were examined in SKOV3 and OVCAR3 human HRR-proficient ovarian cancer cells. Subsequently, the effects of olaparib-Ga on suppression of RRM2 expression, activation of Fe 2+ /reactive oxygen species (ROS)/MAPK and HMOX1 signaling, inhibition of the PI3K/AKT signaling pathway, and cleaved-caspase 3 and BAX protein upregulation were evaluated in order to compare the tumor-suppressive role of olaparib-Ga with pure olaparib.…”