Latest Advances in the Development of Eukaryotic Vaults as Targeted Drug Delivery Systems

Abstract

The use of smart drug delivery systems (DDSs) is one of the most promising approaches to overcome some of the drawbacks of drug-based therapies, such as improper biodistribution and lack of specific targeting. Some of the most attractive candidates as DDSs are naturally occurring, self-assembling protein nanoparticles, such as viruses, virus-like particles, ferritin cages, bacterial microcompartments, or eukaryotic vaults. Vaults are large ribonucleoprotein nanoparticles present in almost all eukaryotic cells. Expression in different cell factories of recombinant versions of the “major vault protein” (MVP) results in the production of recombinant vaults indistinguishable from native counterparts. Such recombinant vaults can encapsulate virtually any cargo protein, and they can be specifically targeted by engineering the C-terminus of MVP monomer. These properties, together with nanometric size, a lumen large enough to accommodate cargo molecules, biodegradability, biocompatibility and no immunogenicity, has raised the interest in vaults as smart DDSs. In this work we provide an overview of eukaryotic vaults as a new, self-assembling protein-based DDS, focusing in the latest advances in the production and purification of this platform, its application in nanomedicine, and the current preclinical and clinical assays going on based on this nanovehicle.

The RNA Methyltransferase NSUN2 and Its Potential Roles in Cancer

“…Vaults are ribonucleoprotein complexes widely associated with the induction of chemoresistance and long-term chemotherapy failure [ 126 ] and for which expression plays a role in preventing apoptosis and regulating autophagy [ 127 , 128 , 129 , 130 ]. Vault complexes are composed primarily of three proteins: a 100-kDa major vault protein (MVP), a 290-kDa telomerase-associated protein 1 (TEP1), and a 193-kDa vault poly (ADP-ribose) polymerase (VPARP) complexed with noncoding vault RNA (vtRNAs) [ 126 ].…”

“…Vaults are ribonucleoprotein complexes widely associated with the induction of chemoresistance and long-term chemotherapy failure [ 126 ] and for which expression plays a role in preventing apoptosis and regulating autophagy [ 127 , 128 , 129 , 130 ]. Vault complexes are composed primarily of three proteins: a 100-kDa major vault protein (MVP), a 290-kDa telomerase-associated protein 1 (TEP1), and a 193-kDa vault poly (ADP-ribose) polymerase (VPARP) complexed with noncoding vault RNA (vtRNAs) [ 126 ]. vtRNAs have been shown to have the ability to recognize chemotherapeutic compounds, such as mitoxantrone, and it has been suggested that the binding of vtRNAs to these chemotherapeutic compounds prevents the drugs from reaching their target sites and consequently in cancer chemoresistance [ 131 , 132 ].…”

Enzyme encapsulation by protein cages

“…Almost all known vaults consist of one major protein component known as the major vault protein (MVP), with minor components including poly(ADP-ribose) polymerase (VPARP), telomerase and small non-translated RNA. 83 Structural and biophysical studies have shown that MVP and VPARP interact through involvement of a particular domain known as interaction domain (INT) present on VPARP. The domain consists of 161 amino acids and resides on the C-terminus of VPARP.…”

“…84 Because of its unique architecture and its large cavity size, the vault cage has been widely used for cargo encapsulation of numerous molecules including therapeutics, small molecules and polymers. 83,85 Recently it was used to load MnP for bioremediation. The enzyme was packaged inside vault by genetically fusing it with INT-domain, and then encapsulation was achieved via high affinity interaction between the INT domain and vault interior.…”

A Tunable Nanoplatform of Nanogold Functionalised with Angiogenin Peptides for Anti-Angiogenic Therapy of Brain Tumours

“…Biological protein-based nanoparticles are advantageous in having biodegradability, bioavailability, and relatively low cost. Many protein nanoparticles, for instance naturally occurring protein cages such as ferritin, are easy to process and can be modified to achieve desired specifications such as size, morphology, and weight [9,10,11]. Natural product-based nanomedicine include, among the most common types of nanoparticles, polymeric micelles, solid lipid nanoparticles, liposomes, inorganic nanoparticles and dendrimers [3,12].…”