Coacervation-Driven Semipermeable Nanoreactors for Enzymatic Cascade-Mediated Cancer Combination Therapy with Enhanced Efficacy.

Utilizing enzyme cascades as a promising approach for targeted cancer therapies holds significant potential, yet its clinical effectiveness is substantially hindered by functional losses during delivery. Complex coacervation emerges as an intriguing strategy for designing functional nanoreactors. In this study, a noteworthy achievement is presented in the development of lactobionic acid-modified tumor microenvironment (TME)-responsive polyelectrolyte complex vesicles (HGS-PCVs) based on bioinspired homopolypeptoids, which serve as a facile, intelligent, and highly efficient nanoreactor tunable for glucose oxidase, hemoglobin, and sorafenib (SRF) to hepatic cancer cells. The TME-responsive permeability of HGS-PCVs enables the selective entry of glucose into their interior, triggering an enzymatic cascade reaction within the tumor. This intricate process generates toxic hydroxyl radicals while concurrently lowering the pH. Consequently, this pH shift enhances the SRF release, effectively promoting ferroptosis and apoptosis in the target cancer cells. Further, the administration of the HGS-PCVs not only initiates immunogenic cell death but also plays a crucial role in inducing the maturation of dendritic cells within lymph nodes. It stimulates an adaptive T-cell response, a crucial mechanism that contributes to impeding the growth of distant tumors in vivo, demonstrating the promising potential of PCVs for cancer immunotherapy.

A Versatile Supramolecular Assembly Platform for Tumor Microenvironment Motivated Drug Release and Ferroptosis Synergistic Therapy.

We report a simplistic approach that employs complexation between poly(N-allylglycine) modified with 3-mercaptoacetic acid (PNAG-COOH) and a series of metal ions to construct a new type of supramolecular architecture with intriguing features that enable a versatile and advanced nanoplatform. In most cases, such complexation results in nanoscale vesicles with superior stability, which differs significantly from the precipitates of conventional carbon-chain polymers and polypeptides. We attribute this to the polar tertiary amide groups in the polypeptoid backbone that offer excellent water affinity and numerous noncovalent molecular interactions. Particularly, the PNAG-COOH/Fe2+ complex can generate reactive oxygen species via a Fenton reaction in the presence of H2O2, thus causing ferroptosis selectively in the tumor cell. In addition, a H2O2-modulated intracellular in situ morphology transition enables prompt release of doxorubicin, representing a synergistic target antitumor efficacy. The prepared supramolecular platforms present promising candidates for many applications, considering the ability to assemble with various metal ions.

Antimicrobial Nanostructured Assemblies with Extremely Low Toxicity and Potent Activity to Eradicate Staphylococcus Aureus Biofilms.

Self-assembled cationic polymeric nanostructures have been receiving increasing attention for efficient antibacterial agents. In this work, a new type of antibacterial agents is developed by preparing pH-dependent nanostructured assemblies from cationic copolypeptoid poly(N-allylglycine)-b-poly(N-octylglycine) (PNAG-b-PNOG) modified with cysteamine hydrochloride ((PNAG-g-NH2 )-b-PNOG) driven by crystallization and hydrophobicity of the PNOG blocks. Due to the presence of confined domains arising from crystalline PNOG, persistent spheres and fiber-like assemblies are obtained from the same polymer upon a heating-cooling cycle. This allows for direct comparison of antimicrobial efficiency of nanostructured assemblies with various morphologies that are otherwise similar. Both nanostructured assemblies exhibit extremely low toxicity to human red blood cells, irrespective of the presence of the hydrophobic block. Enhanced antimicrobial performance of the fiber-like micelles compared to the spheres, which result in high selectivity of the fibers, is shown. Notably, the fiber-like micelles show great efficacy in inhibition of the Staphylococcus aureus (S. aureus) biofilm formations and eradication of the mature biofilms, superior to vancomycin. The micelles also show potent in vivo antimicrobial efficacy in a S. aureus infection mouse skin model. With a systematic study, it is demonstrated that both micelles kill the bacteria through a membrane disruption mechanism. These results imply great potential of polypeptoid assemblies as promising excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a new generation of nanostructured antimicrobials.