Remotely Controllable Supramolecular Nanomedicine for Drug-Resistant Colorectal Cancer Therapy Caused by Fusobacterium nucleatum.

Fusobacterium nucleatum (Fn) existing in the community of colorectal cancer (CRC) promotes CRC progression and causes chemotherapy resistance. Despite great efforts that have been made to overcome Fn-induced chemotherapy resistance by co-delivering antibacterial agents and chemotherapeutic drugs, increasing the drug-loading capacity and enabling controlled release of drugs remain challenging. In this study, a novel supramolecular upconversion nanoparticle (SUNP) is constructed by incorporating a positively charged polymer (PAMAM-LA-CD) with Fn inhibition capacity, a negatively charged platinum (IV) oxaliplatin prodrug (OXA-COOH), upconversion nanoparticle (UCNPs) and polyethylene glycol-azobenzene (PEG-Azo) to enhance drug-loading and enable on-demand drug release for drug-resistant CRC treatment. SUNPs exhibit high drug-loading capacity (30.8%) and good structural stability under normal physiological conditions, while disassembled upon exogenous NIR excitation and endogenous azo reductase in the CRC microenvironment to trigger drug release. In vitro and in vivo studies demonstrate that SUNPs presented good biocompatibility and robust performance to overcome chemoresistance, thereby significantly inhibiting Fn-infected cancer cell proliferation. This study leverages multiple dynamic chemical designs to integrate both advantages of drug loading and release in a single system, which provides a promising candidate for precision therapy of bacterial-related drug-resistant cancers.

Si3N4 Nanofibrous Aerogel with In Situ Growth of SiOx Coating and Nanowires for Oil/Water Separation and Thermal Insulation.

Nanofibrous aerogels constructed by ceramic fiber components (CNFAs) feature lightweight, compressibility, and high-temperature resistance, which are superior to brittle ceramic aerogels assembled from nanoparticles. Up to now, in order to obtain CNFAs with stable framework and multifunctionality such as hydrophobicity and gas absorption, it is necessary to perform binding and surface modification processes, respectively. However, the microstructure as well as properties of CNFAs are deteriorated by the direct addition of binders and modifiers. To tackle these problems, we introduced a unique low-temperature (100 °C) chemical vapor deposition method (LTCVD) to achieve the cross-linking and hydrophobization of Si3N4 CNFA in only one step. More importantly, during the LTCVD process, SiOx coatings and nanowire arrays were in situ formed via vapor-solid (VS) and vapor-liquid-solid (VLS) mechanisms on the surface and intersection of Si3N4 nanofibers, which cemented the aerogel framework, endowed it with hydrophobicity, and improved its oxidation resistance at high temperature. Compared to most of its counterparts, the Si3N4/SiOx CNFA exhibited better mechanical properties, higher capability of oil/water separation (33-76 g·g-1), lower thermal conductivity (0.0157 W/m·K-1), and superior structural stability in a wide temperature range of -196-1200 °C. This work not only presents an excellent Si3N4/SiOx CNFA for the first time but also provides fresh insights for the exquisite preparation strategy of CNFAs.

A dendritic polyamidoamine supramolecular system composed of pillar[5]arene and azobenzene for targeting drug-resistant colon cancer.

Fusobacterium nucleatum caused drug-resistant around tumor sites often leads to the failure of chemotherapy during colorectal cancer (CRC) treatment. Multifunctional cationic quaternary ammonium materials have been widely used as broad-spectrum antibacterial agents in antibacterial and anticancer fields. Herein, we design a smart supramolecular quaternary ammonium nanoparticle, namely quaternary ammonium PAMAM-AZO@CP[5]A (Q-P-A@CP[5]A), consisting of azobenzene (AZO)-conjugated dendritic cationic quaternary ammonium polyamidoamine (PAMAM) as the core and carboxylatopillar[5]arene (CP[5]A)-based switch, for antibacterial and anti-CRC therapies. The quaternary ammonium-PAMAM-AZO (Q-P-A) core endows the supramolecular system with enhanced antibacterial and anticancer properties. -N+CH3 groups on the surface of Q-P-A are accommodated in the CP[5]A cavity under normal conditions, which significantly improves the biocompatibility of Q-P-A@CP[5]A. Meanwhile, the CP[5]A host can be detached from -N+CH3 groups under pathological conditions, achieving efficient antibacterial and antitumor therapies. Furthermore, azoreductase in the tumor site can break the -NN- bonds of AZO in Q-P-A@CP[5]A, leading to the morphology recovery of supramolecular nanoparticles and CRC therapy through inducing cell membrane rupture. Both in vitro and in vivo experiments demonstrate that Q-P-A@CP[5]A possesses good biocompatibility, excellent antibacterial effect, and CRC treatment capability with negligible side effects. This supramolecular quaternary ammonium system provides an effective treatment method to overcome chemotherapy-resistant cancer caused by bacteria.

Construction of traceable cucurbit[7]uril-based virus-mimicking quaternary complexes with aggregation-induced emission for efficient gene transfection.

Construction of an efficient cationic gene delivery system with low cytotoxicity, high transfection efficacy, as well as gene tracking function remains a major challenge in gene therapy. Fabrication of simple and reversible nanocomplexes based on host-guest interaction provides an opportunity to construct stimuli-responsive intelligent supramolecular systems. Inspired by the hierarchical structure of viruses, a novel virus-mimicking PG/CB/TPE/DNA gene delivery system is developed via a multistep noncovalent self-assembly process between pDNA and the preformed PG/CB/TPE complexes based on the host-guest interaction between cucurbit[7]uril (CB[7]) and the protonated diamine group in the poly(glycidyl methacrylate)s derivative (PG), as well as the electrostatic interaction between para-carboxyl functionalized tetraphenylethylene (TPE) and cationic PG. The developed efficient multifunctional gene delivery system exhibits stimuli responsive characteristics and aggregation-induced emission phenomena, thereby enabling gene delivery pH responsiveness and traceability. Moreover, the introduction of TPE and CB[7] endows the self-assembled PG/CB/TPE/DNA complexes with virus-mimicking architecture and properties such as low cytotoxicity, high stability, excellent endosomal escape, and efficient transfection, which are expected to be used as a promising gene delivery system.

Multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness for precise cancer therapy.

Near-infrared (NIR) light-induced photothermal agent-based stimuli-responsive materials have attracted great interest from researchers. However, the highly smart release with precise control by NIR light is not yet well established because of the lack or inadequacy of intelligent release systems, such as premature release of drug and/or photothermal agent. Herein, we put forward a novel and convenient strategy to synthesize cyanine dye-functionalized polymeric materials, where cyanine dye was schemed to attach to polymeric materials by copolymerization, endowing the polymeric materials with NIR light-responsive photothermal property and fluorescent nature for real-time imaging of endocytosis and intracellular trafficking of nanovehicles. Meanwhile, the chemotherapy drug DOX was introduced into the cyanine-containing polymeric materials via formation of dynamic covalent hydrazone bond to circumvent the blood circulation barrier. The nanovehicles displayed fine pH/NIR light-controlled drug release and excellent tumor intracellular drug transposition, which were ulteriorly combined with photo-triggered hyperthermia for enhanced antitumor effect. Therefore, this multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness provides a novel strategy to attain highly smart drug delivery for precise cancer therapy.

Hyaluronic acid/PEGylated amphiphilic nanoparticles for pursuit of selective intracellular doxorubicin release.

Polyethylene glycol (PEG)-lyted cationic amphiphilic copolymers were employed as complexing agents with biocompatible anionic hyaluronic acid (HA) for the controlled release of doxorubicin (DOX). The overexpressed receptors to HA in a variety of cancerous cells enable preferential endocytosis of the HA-functionalized nanoparticles. Moreover, introduction of HA is supposed to diminish the unfavorable non-specific reactions in the biological milieu. Particularly, the drastic positive charge was validated post-endocytosis as a consequence of our strategic molecular design for the promotion of positive charges of cationic components. This deshielding effect of the anionic hyaluronic acid by endogenous hyaluronidase in endosomes and demotion of PEG at the endosome acid microenvironment consequently results in the structural rearrangement and favorable reaction of the resulting positive-charged structure with the intracellular species and structures, ultimately giving rise to liberation of the doxorubicin for the subsequent molecular pharmaceutic consequences. Simultaneously, the system containing quaternary ammonium salt and hydrophobic n-octyl acrylate (OA) possesses considerable antibacterial ability to alleviate anti-cancer drugs resistance. This delivery system is intended to overcome the intratumor bacteria-induced tumor resistance.

Construction of Bovine Serum Albumin/AIE-Based Quaternary Complexes for Efficient Gene Transfection.

High transfection efficiency and superior cell imaging are required for cationic polymers-based gene delivery system to afford high therapeutic effect but its high toxicity and unstable cell imaging are easily ignored. In this study, cationic amino poly(glycerol methacrylate) derivative (PGMA-EDA) is used to incorporate bovine serum albumin (BSA) and aggregation-induced emission (AIE) molecular (tetraphenylethylene derivatives, TPE) as an efficient carrier for gene transfection and intracellular imaging. The obtained polymer/pDNA-TPE/BSA (PDTB) quaternary nanoparticles (NPs) not only exhibit efficient gene transfection but also show excellent biocompatibility. After inclusion of TPE/BSA (TB) NPs, BSA promoted dissociation of the complexes upon being protonated and the lipophilic TPE-reduced endosomal membrane stability, which enhanced endosomal escape of pDNA payload, finally resulting in an excellent gene transfection. On the other hand, less positive surface charge of PDTB NPs than that of the binary PD complexes, as well as the addition of biocompatible BSA, both factors contribute to the improved cell viability. Moreover, the AIE feature of TPE compared to aggregation-caused quenching character of conventional fluorophores enables the complex with stably tracking the delivery of pDNA into cancer cells. Therefore, the newly developed PDTB complexes may be a promising candidate vector for traceable, safe, and effective gene delivery.

Near-infrared AIEgen-functionalized and diselenide-linked oligo-ethylenimine with self-sufficing ROS to exert spatiotemporal responsibility for promoted gene delivery.

Reversible stabilities are required for therapeutic (e.g. DNA) delivery systems to afford adequate stability in the journey to therapeutic targets but make the systems susceptible to structural disassembly and the liberation of their therapeutic payloads. For this purpose, we attempted to synthesize an oligo-ethyleneimine (OEI)-crosslinked polycation, characterized with self-sufficing reactive oxygen species (ROS) by virtue of a functional aggregation-induced emissive (AIE) component (with good near-infrared imaging functions) and an ROS-labile diselenide linkage. The strategic AIE component was capable of exerting facile ROS production upon convenient daylight irradiation (unprecedented ROS-producing efficiency of 80.14%), consequently helping to activate an endosomal escape functionality and the fragmentation of the OEI-crosslinked polycation into low molecular weight OEI products. Consequently, the engineered capabilities enabled the spatiotemporal control of the stabilities of the electrostatic-based DNA self-assembled formation so that it was adequately stable in the gene transportation journey to the targets but could reverse the stabilities to liberate pDNA to execute the subsequent biological processes, evidenced by the disassociation of the near-infrared emission of AIEgen and Cy5-pDNA. Therefore, our devised strategies provided tempting design implications for utilizing daylight as an impetus for the intracellular delivery of functional molecules, and thus could be developed further to find broad utilities in the transportation of a variety of biological substances in therapeutic applications.