Self-Assembly of Poly(Amino Acid)s Mediated by Secondary Conformations.

Self-assembly of block copolymers has recently drawn great attention due to its remarkable performance and wide variety of applications in biomedicine, biomaterials, microelectronics, photoelectric materials, catalysts, etc. Poly(amino acid)s (PAAs), formed by introducing synthetic amino acids into copolymer backbones, are able to fold into different secondary conformations when compared with traditional amphiphilic copolymers. Apart from changing the chemical composition and degree of polymerization of copolymers, the self-assembly behaviors of PAAs could be controlled by their secondary conformations, which are more flexible and adjustable for fine structure tailoring. In this article, we summarize the latest findings on the variables that influence secondary conformations, in particular the regulation of order-to-order conformational changes and the approaches used to manage the self-assembly behaviors of PAAs. These strategies include controlling pH, redox reactions, coordination, light, temperature, and so on. Hopefully, we can provide valuable perspectives that will be useful for the future development and use of synthetic PAAs.

Photoallosteric Polymersomes toward On-Demand Drug Delivery and Multimodal Cancer Immunotherapy.

Allosteric transitions can modulate the self-assembly and biological function of proteins. It remains, however, tremendously challenging to design synthetic allosteric polymeric assemblies with spatiotemporally switchable hierarchical structures and functionalities. Here, a photoallosteric polymersome is constructed that undergoes a rapid conformational transition from ß-sheet to α-helix upon exposure to near-infrared light irradiation. In addition to improving nanoparticle cell penetration and lysosome escape, photoinduced allosteric behavior reconstructs the vesicular membrane structure, which stimulates the release of hydrophilic cytolytic peptide melittin and hydrophobic kinase inhibitor sorafenib. Combining on-demand delivery of multiple therapeutics with phototherapy results in apoptosis and immunogenic death of tumor cells, remold the immune microenvironment and achieve an excellent synergistic anticancer efficacy in vivo without tumor recurrence and metastasis. Such a light-modulated allosteric transition in non-photosensitive polymers provides new insight into the development of smart nanomaterials for biosensing and drug delivery applications.

Protein-Inspired Polymers with Metal-Site-Regulated Ordered Conformations.

Metal ions play critical roles in facilitating peptide folding and inducing conformational transitions, thereby impacting on the biological activity of many proteins. However, the effect of metal sites on the hierarchical structures of biopolymers is still poorly understood. Herein, inspired by metalloproteins, we report an order-to-order conformational regulation in synthetic polymers mediated by a variety of metal ions. The copolymers are decorated with clinically available desferrioxamine (DFO) as an exogenous ligand template, which presents a geometric constraint toward peptide backbone via short-range hydrogen bonding interactions, thus dramatically altering the secondary conformations and self-assembly behaviors of polypeptides and allowing for a controllable ß-sheet to α-helix transition modulated by metal-ligand interactions. These metallopolymers could form ferritin-inspired hierarchical structures with high stability and membrane activity for efficient brain delivery across the blood-brain barrier (BBB) and long-lasting magnetic resonance imaging (MRI) in vivo.

Ordered Conformation-Regulated Vesicular Membrane Permeability.

In nature, the folding and conformation of proteins can control the cell or organelle membrane permeability and regulate the life activities. Here we report the first example of synthetic polypeptide vesicles that regulate their permeability via ordered transition of secondary conformations, in a manner similar to biological systems. The polymersomes undergo a ß-sheet to α-helix transition in response to reactive oxygen species (ROS), leading to wall thinning without loss of vesicular integrity. The change of membrane structure increases the vesicular permeability and enables specific transport of payloads with different molecular weights. As a proof-of-concept, the polymersomes encapsulating enzymes could serve as nanoreactors and carries for glucose-stimulated insulin secretion in vivo inspired by human glucokinase, resulting in safe and effective treatment of type 1 diabetes mellitus in mouse models. This study will help understand the biology of biomembranes and facilitate the engineering of nanoplatforms for biomimicry, biosensing, and controlled delivery applications.