Regulation of Proteins to the Cytosol Using Delivery Systems with Engineered Polymer Architecture

Abstract

Intracellular protein delivery enables selective regulation of cellular metabolism, signaling, and development through introduction of defined protein quantities into the cell. Most applications require that the delivered protein has access to the cytosol, either for protein activity or as a gateway to other organelles such as the nucleus. The vast majority of delivery vehicles employ an endosomal pathway however, and efficient release of entrapped protein cargo from the endosome remains a challenge. Recent research has made significant advances toward efficient cytosolic delivery of proteins using polymers, but the influence of polymer architecture on protein delivery is yet to be investigated. Here, we developed a family of dendronized polymers that enable systematic alterations of charge density and structure. We demonstrate that while modulation of surface functionality has a significant effect on overall delivery efficiency, the endosomal release rate can be highly regulated by manipulating polymer architecture. Notably, we show that large, multivalent structures cause slower sustained release, while rigid spherical structures result in rapid burst release.

Role of Ionic Strength in the Formation of Stable Supramolecular Nanoparticle–Protein Conjugates for Biosensing

“…Monolayer-protected gold nanoparticles (AuNPs) have been extensively investigated to disclose their unique and diverse properties. [1][2][3][4][5] AuNPs have already shown great potential in applications, including chemosensing (i.e., small molecule detection in solution) [6,7], biosensing [8][9][10], catalysis (nanozymes) [11][12][13] and transport of chemical species in biological environments and cells (e.g., drug delivery) [14][15][16]. Inorganic nanoparticles can be engineered to possess physiochemical properties for specific applications, e.g., their shape [17] and size [18] can be tuned to define nanoparticle properties.…”

Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

“…Polymeric materials, particularly hydrogels, have been described as the preferred choice due to characteristics such as hydrophilic porous matrix, flexibility, high biocompatibility and biodegradability, prolonged consistency, userfriendliness, low cost, and ease of access [20][21][22]. To aid in finding its optimal parameters, there have been several experimental and in silico studies that confirm a strong dependency on solubility, high degree of functional design space, surface multivalency, facile chemical modification, high stability, and ease of integration with other materials such as lipids and nanoparticles [23][24][25][26]. For instance, Mdlovu et al designed a magnetic nanocarrier composed of iron oxide magnetic nanoparticles coated with Pluronic F127 for the delivery of the chemotherapeutic drug doxorubicin (DOX) in neuroblastoma where the drug release profile showed a pH-dependent drug release where more DOX was released under acidic environments than in neutral conditions [27].…”

Tetraphenylethylene‐Featured Fluorescent Supramolecular Nanoparticles for Intracellular Trafficking of Protein Delivery and Neuroprotection

“…The dysfunction or abnormal expression of protein within cells is closely associated with a large variety of diseases, including cancers and neurodegenerative diseases [3] . Therefore, supplementing disease cells with functional proteins is an appealing approach to regulate cell signalling, providing an innovative strategy to manipulate cellular function for disease treatment [4, 5] . The inability of most proteins to spontaneously cross the lipid bilayer of mammalian cells, however, greatly limits current protein therapeutics to target extracellular components [6] .…”