Syringeable immunotherapeutic nanogel reshapes tumor microenvironment and prevents tumor metastasis and recurrence.

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity.

Peroxisome-targeted Supramolecular Nanoprobes Assembled with Pyrene-labelled Peptide Amphiphiles.

Despite the versatile metabolic functions of peroxisomes such as lipid synthesis and fatty acid oxidation and their relevance to genetically inherited diseases, namely, peroxisome biogenesis disorders and peroxisomal enzyme deficiency, there is not much research on peroxisome-targeting therapeutics. Herein we present supramolecular nanostructured probes based on the self-assembly of peptide amphiphiles (PAs) having peroxisome-targeting ability in mammalian cells. The PA was designed to include the peroxisome-targeting tripeptide (SKL) and a fluorescent dye (pyrene). It was revealed that the presence of the SKL-appended carboxyl terminal group of PA, the extent of α-helical nature of the peptide block, and the fibrillar morphology of nano-assemblies affected the targeting efficiency of PA supramolecular nanoprobe. The simple modification of PAs by the peroxisome-targeting strength prediction showed an enhanced peroxisome specificity, as expected. This work provides important insights into designing subcellular organelle-targeting nanoparticles for next-generation nanomedicines.

Multicompartment Vesicles Formation by Emulsification-Induced Assembly of Poly(ethylene oxide)-block-poly(ε-caprolactone) and Their Dual-Loading Capability.

Emulsification-induced assembly is employed to allow structural diversity in nanoaggregates of a biocompatible amphiphilic polymer, poly(ethylene oxide)-block-poly(ε-caprolactone). Onion-like vesicles are efficiently produced by tuning the interfacial instability of the oil-in-water emulsion. The increase in the polymer concentration and use of the organic solvents with a low interfacial tension between water and the oil phase lead to a strong tendency of emulsion droplets to generate the onion-like vesicles. The vesicular networks and fibers are also obtained by controlling the concentration and type of the surfactant, respectively. Interestingly, the onion-like vesicles composed of alternating walls and water channels and the vesicular networks originated from a string of vesicles show dual-loading ability for hydrophobic and hydrophilic dyes but slightly different loading capacities. This result indicates that the development of a methodology to fabricate well-defined, unique nanostructures, such as multivesicular and multilamellar nanostructures, and subsequent elucidation of their structure-property relationships can provide useful guidance in the design of novel biomedical materials.

Structure-Dependent Antimicrobial Theranostic Functions of Self-Assembled Short Peptide Nanoagents.

Gadolinium (Gd[III])-based nanoaggregates are potential noninvasive magnetic resonance imaging (MRI) probes with excellent spatial and temporal resolution for cancer diagnosis. Peptides conjugated with Gd3+ can aid in supramolecular scaffolding for MRI nanoagents because of their inherent biocompatibility and degradability. We report here a strategy to tune the MR relaxivity of tumor cell-targeted nanoagents and enhance the antimicrobial and anticancer activities of nanoagents based on rationally designed antimicrobial peptide (AMP) assembly. A tripeptide with glycyl-l-histidyl-l-lysine (GHK) capable of Gd3+ chelation was attached to short AMPs containing pyrazole amino acids that spontaneously assembled as a function of the number of hydrophobic amino acid residues and the peptide length of AMPs. Aqueous coassembly of GHK with tumor-targeting, cyclic arginine-glycine-aspartic acid (cRGD)-tagged AMPs resulted in the formation of micelles, fibrils, vesicles, sheets, and planar networks. Interestingly, the two-dimensional planar network nanostructure showed less antibacterial activity and tumor cell cytotoxicity but greater drug loading/delivery and magnetic resonance signaling than micelles because of its intrinsic structural characteristics. This study can provide a rational approach for the design and fabrication of clinically useful nanoagents.

Mitochondria localization induced self-assembly of peptide amphiphiles for cellular dysfunction.

Achieving spatiotemporal control of molecular self-assembly associated with actuation of biological functions inside living cells remains a challenge owing to the complexity of the cellular environments and the lack of characterization tools. We present, for the first time, the organelle-localized self-assembly of a peptide amphiphile as a powerful strategy for controlling cellular fate. A phenylalanine dipeptide (FF) with a mitochondria-targeting moiety, triphenyl phosphonium (Mito-FF), preferentially accumulates inside mitochondria and reaches the critical aggregation concentration to form a fibrous nanostructure, which is monitored by confocal laser scanning microscopy and transmission electron microscopy. The Mito-FF fibrils induce mitochondrial dysfunction via membrane disruption to cause apoptosis. The organelle-specific supramolecular system provides a new opportunity for therapeutics and in-depth investigations of cellular functions.Spatiotemporal control of intracellular molecular self-assembly holds promise for therapeutic applications. Here the authors develop a peptide consisting of a phenylalanine dipeptide with a mitochondrial targeting moiety to form self-assembling fibrous nanostructures within mitochondria, leading to apoptosis.