Engineering protein self-assembling in protein-based nanomedicines for drug delivery and gene therapy

Abstract

Lack of targeting and improper biodistribution are major flaws in current drug-based therapies that prevent reaching high local concentration of the therapeutic agent. Such weaknesses impose the administration of high drug doses, resulting in undesired side effects, limited efficacy and enhanced production costs. Currently missing nanosized containers, functionalized for specific cell targeting will be then highly convenient for the controlled delivery of both conventional and innovative drugs. In an attempt to fill this gap, health-focused nanotechnologies put under screening a growing spectrum of materials as potential components of nanocages, whose properties can be tuned during fabrication. However, most of these materials pose severe biocompatibility concerns. We will revise here how proteins, the most versatile functional macromolecules, can be conveniently exploited and adapted by conventional genetic engineering as efficient building blocks of fully compatible nanoparticles for drug delivery, and how selected biological activities can be recruited to mimic viral behavior during infection. Although engineering of protein self-assembling is still excluded from fully rational approaches, the exploitation of protein nano-assemblies occurring in

Sheltering DNA in self-organizing, protein-only nano-shells as artificial viruses for gene delivery

“…36 In a more versatile approach, modular proteins containing cationic stretches for nucleic acid binding and condensation, as well as other functional segments such as cell penetrating peptides, ligands or nuclear localization signals, have been under continuous design to recruit virus-like functions in single-chain molecules. [37][38][39][40] However, despite the functional versatility of these constructs they fail to reach ordered nanoscale structures, in most cases being the DNA the main driving force of the polyplexe architecture. 11 In fact, the assembly of viral capsids results from a complex combination of intermolecular interactions including hydrophobic, electrostatic, van der Waals, and hydrogen bonds 41 that are excluded from a rational design in the novo designed recombinant proteins.…”

Bottom‐Up Instructive Quality Control in the Biofabrication of Smart Protein Materials

“…Apart from plain therapeutic cytokines, hormones, enzymes, and antibodies, a plethora of more elaborate protein structures with varying complexity have been developed as nanoconjugates for drug delivery including nab‐paclitaxel, denileukin diftitox, poly(ethylene glycol) modified adenosine deaminase (PEG‐ADA), and pegaspargase . Recent developments in the engineering of protein self‐assembly and the expanding catalogs of homing peptides offer clues for the design and construction of smart protein nanostructures intended as functional substrates in regenerative medicine or as vehicles for the cell‐targeted delivery of payload imaging agents and drugs . Most of these applications are based on specific interactions between peptidic ligands displayed on the material's surface, and surface‐exposed receptors on the membrane of target cells, targeting internalization or signaling.…”

Peptide‐Based Nanostructured Materials with Intrinsic Proapoptotic Activities in CXCR4+ Solid Tumors

“…Among the diversity of materials under investigation as drug carriers, including metals, ceramics, polymers, and carbon nanotubes, proteins offer unique properties regarding biocompatibility and degradability, that in the context of rising nanotoxicological concerns, make them especially appealing. As the engineering of protein self‐assembling into nanostructured materials is rapidly progressing and the control over the final geometry and physicochemical properties becomes tighter, protein materials are gaining functional and structural versatility as vehicles from chemically coupled drugs. However, many protein species are, themselves, efficient drugs usable in human therapy, as attested by more than 400 protein‐based products approved by main medicines agencies .…”