A gene delivery system with autophagy blockade for enhanced anti-angiogenic therapy against Fusobacterium nucleatum-associated colorectal cancer.

Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum (F. nucleatum) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum-associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3'-diaminodipropylamine-pendant poly(ß-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum-colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum-resident CRC. STATEMENT OF SIGNIFICANCE: Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum. To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum-associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum-resident CRC.

Engineering lauric acid-based nanodrug delivery systems for restoring chemosensitivity and improving biocompatibility of 5-FU and OxPt against Fn-associated colorectal tumor.

Colorectal cancer (CRC) occurs in the colorectum and ranks second in the global incidence of all cancers, accounting for one of the highest mortalities. Although the combination chemotherapy regimen of 5-fluorouracil (5-FU) and platinum(IV) oxaliplatin prodrug (OxPt) is an effective strategy for CRC treatment in clinical practice, chemotherapy resistance caused by tumor-resided Fusobacterium nucleatum (Fn) could result in treatment failure. To enhance the efficacy and improve the biocompatibility of combination chemotherapy, we developed an antibacterial-based nanodrug delivery system for Fn-associated CRC treatment. A tumor microenvironment-activated nanomedicine 5-FU-LA@PPL was constructed by the self-assembly of chemotherapeutic drug derivatives 5-FU-LA and polymeric drug carrier PPL. PPL is prepared by conjugating lauric acid (LA) and OxPt to hyperbranched polyglycidyl ether. In principle, LA is used to selectively combat Fn, inhibit autophagy in CRC cells, restore chemosensitivity of 5-FU as well as OxPt, and consequently enhance the combination chemotherapy effects for Fn-associated drug-resistant colorectal tumor. Both in vitro and in vivo studies exhibited that the tailored nanomedicine possessed efficient antibacterial and anti-tumor activities with improved biocompatibility and reduced non-specific toxicity. Hence, this novel anti-tumor strategy has great potential in the combination chemotherapy of CRC, which suggests a clinically relevant valuable option for bacteria-associated drug-resistant cancers.

NIR-II Regulation of Mitochondrial Potassium Channel with Dual-Targeted Conjugated Oligomer Nanoparticles for Efficient Cancer Theranostics In Vivo.

Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties are designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060 nm laser irradiation, the mitochondria-located nanoparticles photothermally release a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles and proposes an effective therapeutic mechanism for malignant tumors.

Iron-Coordinated L-Lysine-Based Nanozymes with High Peroxidase-like Activity for Sensitive Hydrogen Peroxide and Glucose Detection.

It is crucial to develop sensitive and accurate sensing strategies to detect H2O2 and glucose in biological systems. Herein, biocompatible iron-coordinated L-lysine-based hydrogen peroxide (H2O2)-mimetic enzymes (Lys-Fe-NPs) were prepared by precipitation polymerization in aqueous solution. The coordinated Fe2+ ion acted as centers of peroxidase-like enzymes of Lys-Fe-NPs, and the catalytic activity was evaluated via the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2. Therefore, a sensitive colorimetric detection sensor for H2O2 was constructed with a linear range of 1 to 200 µM and a detection limit of 0.51 µM. The same method could also be applied to highly sensitive and selective detection of glucose, with a linear range of 0.5 to 150 µM and a detection limit of 0.32 µM. In addition, an agarose-based hydrogel biosensor colorimetric was successfully implemented for visual assessment and quantitative detection of glucose. The design provided a novel platform for constructing stable and nonprotein enzyme mimics with lysine and showed great potential applications in biorelevant assays.

Near Infrared-Activatable Methylene Blue Polypeptide Codelivery of the NO Prodrug via π-π Stacking for Cascade Reactive Oxygen Species Amplification-Mediated Photodynamic Therapy.

The application of photodynamic therapy (PDT) has attracted remarkable interest in cancer treatment because of the advantages of noninvasiveness and spatiotemporal selectivity. However, the PDT efficiency is considerably limited by photosensitizer (PS) quenching and severe hypoxia in solid tumors. Herein, a kind of near infrared (NIR)-activatable methylene blue (MB) peptide nanocarrier was developed for codelivery of nitric oxide (NO) prodrug JSK, expecting a cascade of reactive oxygen species (ROS) amplification-mediated antitumor PDT. In detail, MB was conjugated to water-soluble polyethylene glycol-polylysine (PEG-PLL) through NIR-photocleavable 10-N-carbamoyl bonds, and the subsequent amphiphilic conjugates (mPEG-PLL-MB) self-assembled into nanoparticles (NPs), which allowed JSK codelivery via π-π stacking interactions. MB in quenched state in mPEG-PLL-MB/JSK NPs could be photoactivated by NIR light locoregionally in a controlled manner due to the photocleavage of carbamoyl bonds. Apart from ROS production, assembly disturbance and even disintegration of mPEG-PLL-MB/JSK occurred along with MB activation that subsequently freed JSK, which was further triggered by intracellularly overexpressed glutathione (GSH) and glutathione S-transferase (GST) to sustain the release of NO. NO then served as a hypoxia relief agent through inhibition of cellular respiration to economize O2, cooperating with MB activation and GSH depletion, which synergistically enabled a cascade of ROS amplification to augment PDT for mitochondrial apoptosis-mediated tumor inhibition in vitro and in vivo. Therefore, this pioneering strategy of cascade amplification of ROS addressed the key issues of PS inactivation, hypoxia resistance, and ROS neutralization in a three-pronged approach, which hold great promise in efficient antitumor PDT.

Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer.

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX2 NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX2) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX2 NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX2 in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.

Cyclopropenium Cationic-Based Covalent Organic Polymer-Enhanced Poly(ethylene oxide) Composite Polymer Electrolyte for All-Solid-State Li-S Battery.

Cyclopropenium cationic-based covalent organic polymer (iCP@TFSI) was successfully prepared through the SN2 reaction and ion replacement process, which can be incorporated into the PEO/LiTFSI matrix as a filler. The obtained solid-state polymer electrolytes were utilized for an all-solid-state lithium-sulfur (Li-S) battery. Padding iCP@TFSI into the PEO matrix not only has a positive influence on both the ionic conductivity and the mechanical capacity of solid-state polymer electrolytes but also increases the stability of the lithium metal anode, which essentially improves the overall cycling ability of all-solid-state Li-S batteries. Among the membranes attained, the PEO-10%iCP@TFSI electrolyte displays the best ionic conductivity up to 1.2 × 10-3 S·cm-1 at 80 °C. The symmetrical lithium battery exhibits higher cycle stability (600 h) due to the higher mechanical properties related to more stable lithium metal interfaces. The Li-S battery based on the PEO-10%iCP@TFSI electrolyte exhibits excellent electrochemical performance with better Coulombic efficiency and outstanding cycling stability. Its capacity is maintained at 490 mAh·g-1 after 500 cycles at 1 C with a 0.032% decay rate each cycle, and the Coulombic efficiency is close to 100% during the whole cycling.

Cascaded amplification of intracellular oxidative stress and reversion of multidrug resistance by nitric oxide prodrug based-supramolecular hydrogel for synergistic cancer chemotherapy.

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