Constraint Coupling of Redox Cascade and Electron Transfer Synchronization on Electrode-Nanosensor Interface for Repeatable Detection of Tumor Biomarkers.

Quantitative analysis of up-regulated biomarkers in pathological tissues is helpful to tumor surgery yet the loss of biomarker extraction and time-consuming operation limited the accurate and quick judgement in preoperative or intraoperative diagnosis. Herein, an immobilization-free electrochemical sensing platform is developed by constraint coupling of electron transfer cascade on electrode-nanosensor interface. Specifically, electrochemical indicator (Ri)-labeled single-stranded DNA on electroactive nanodonor (polydopamine, PDA) can be responsively detached by formation of DNA complex through the recognition and binding with targets. By applying the oxidation potential of Ri, nanosensor collisions on electrode surface trigger a cascade redox cycling of PDA and Ri through synchronous electron transfer, which boost the amplification of current signal output. The developed nanosensor exhibit excellent linear response toward up-regulated biomarkers (miRNA-21, ATP, and VEGF) with low detection limits (32 fM, 386 pM, and 2.8 pM). Moreover, background influence from physiological interferent is greatly reduced by restricted electron transfer coupling on electrode. The practical applicability is illustrated in sensitive and highly repeatable profiling of miRNA-21 in lysate of tumor cells and tumor tissue, beneficial for more reliable diagnosis. This electrochemical platform by employing electron transfer cascades at heterogeneous interfaces offers a route to anti-interference detection of biomarkers in tumor tissues.

Catalytically proficient ceria nanodots supported on redox-active mesoporous hosts for treatment of inflammatory bowel disease via efficient ROS scavenging.

Ceria nanozyme-based ROS scavengers have shown great potential in the treatment of inflammatory bowel disease (IBD) through microenvironment regulation. However, the currently developed nanotherapeutics suffer from difficulties in concomitantly achieving small sizes and stable interparticle dispersion which is pivotal to sufficient oxygen vacancies facilitating electron transfer and oxygen storage in the dynamic cycling of Ce3+/Ce4+ redox pairs. Herein, a hybrid nanosystem consisting of ceria nanodots supported on redox-active mesoporous hosts was developed to address the challenge of ROS scavenging, in particular the efficient downregulation of the readily renewable, highly concentrated H2O2 species. Specifically, Ce4+ ions oxidized from Ce3+ in weakly basic solution were captured and reduced in time by the abundant catechols on the mesoporous polydopamine nanoparticles. This led to strong restriction of ceria growth (∼2.8 nm) in the ion precipitation process and efficient maintenance of the Ce3+/Ce4+ ratio at a high value of 1.59 which is 4.8 fold higher than that of homogeneously nucleated ceria nanoparticles. Through this design, the nanohybrid showed an attractive catalytic performance in scavenging multiple ROS species, particularly the fast and recyclable conversion of H2O2. Thereby, significant suppression of the inflammatory cytokine/chemokine secretion was achieved by inhibiting the activation of NF-κB signaling pathways (5.1 fold higher as compared to those of pristine ceria nanoparticles), upregulating the Nrf2 signaling pathway, and reducing the proportion of M1 macrophages at IBD sites. Therapeutic efficiency was also demonstrated by the effective repair of the intestinal mucosal barrier by recovering the tight junction integrity in vivo. This study sheds light on the employment of redox-active hosts to support ceria catalysts for advancing anti-inflammation applications by boosting ROS scavenging performance.

Flower-like Nanozyme with Highly Porous Carbon Matrix Induces Robust Oxidative Storm against Drug-Resistant Cancer.

Reactive oxygen species (ROS) generators are sparking breakthroughs in sensitization and treatment of therapy-resistant tumors, yet the efficacy is drastically compromised by limited substrate concentrations, short lifetimes of free radicals, and restricted oxidative damage. Herein, a flower-like nanozyme with highly permeable leaflets accommodating catalytic metal sites was developed to address the challenges by boosting substrate and product accessibility. In the formation of a zeolite imidazole framework, cobalt ions promoted catalytic polymerization and deposition of polydopamine. The polymers acted as a stiffener for preventing framework collapse and maneuvering pore reopening during carbonization. The cobalt single-atom/cluster sites in the highly porous matrix generated peroxidase/oxidase-like activities with high catalytic efficiency (Kcat/Km) up to 6 orders of magnitude greater than that of conventional nano-/biozymes. Thereby, a robust ROS storm induced by selective catalysis led to rapid accumulation of oxidative damage and failure of antioxidant and antiapoptotic defense synchronization in drug-resistant cancer cells. By synergy of a redox homeostasis disrupter co-delivered, a significantly high antitumor efficiency was realized in vivo. This work offers a route to kinetically favorable ROS generators for advancing the treatment of therapy-resistant tumors.

Combination wound healing using polymer entangled porous nanoadhesive hybrids with robust ROS scavenging and angiogenesis properties.

Nanoadhesives can achieve tight wound closure by connecting biomacromolecules from both sides. However, previously developed adhesive systems suffered from suboptimal wound healing efficiency due to the lack of interparticle cohesion, sufficient reactive oxygen species (ROS)-scavenging sites, and angiogenesis consideration. Herein, we developed a polymer entangled porous nanoadhesive system to address the above challenge by synergy of three functional components. Firstly, hybrid mesoporous silica nanoparticles with highly integrated polydopamine (MS-PDA) were prepared by templated synthesis. The entangling between PVA polymer and MS-PDA contributed to much stronger cohesion between nanoparticles, which led to 75% larger adhesion strength. As confirmed by in vitro and in vivo evaluations, the highly exposed catechol groups boosted the scavenging activity of ROS (1.8-4.1 fold enhancement as compared with nonporous counterpart). Consequently, more macrophages exhibited anti-inflammatory phenotype, leading to 2-2.6 fold lower pro-inflammatory cytokine levels. Moreover, the sustained release of bioactive SiO44- by the disintegration of nanoparticles contributed to ∼3-fold higher expression of VEGF and enhanced new blood vessel formation, as well as better wound repair. This platform can provide a new paradigm for developing multifunctional nanoadhesive systems in treating skin wounds. STATEMENT OF SIGNIFICANCE: PVA polymer entangled mesoporous nanoadhesives of polydopamine (PDA)/silica hybrids with the combination of excellent wound closure effect, boosted ROS-scavenging activity, and significant angiogenesis ability were developed for improving the suboptimal skin wound healing efficiency. This strategy not only greatly advances our ability to rationally integrate repairing elements in nanoadhesives for manipulating combined processes of interfacial events during wound healing, but also offers general implications toward application of polymers to reinforce the adhesion strength in nanoadhesive systems. In addition, our findings on the impacts of pore effects mediated ROS species conversion and polymer entanglement may also trigger great interests and facilitate the development/broad application of therapeutic adhesives.

Melanin Nanoparticle-Actuated Redox-State Perturbation and Temporally Photoactivated Thermal Stress for Synergistic Tumor Therapy.

The elevation of antioxidant defense systems by adaptation response to localized reactive oxygen species (ROS) accumulation may confer resistance to excessive oxidative stress and cause therapeutic lethality. Herein, a highly effective tumor therapy is developed through perturbation in cellular redox homeostasis. Specifically, metal-ion-assisted oxidation polymerization of the melanin precursor (l-DOPA) whose carboxyl groups exert a charge-shielding effect leads to the formation of catechol-rich but quinone-deficient nanoparticles (NPs). These NPs possess appreciable ROS-scavenging ability, and particularly the raised quinone group levels in oxidized products can then trigger subsequent depletion of antioxidative species (GSH) and, in turn, the redox-cycle consumption of catechol/quinone groups. After incubating with cells, varying degrees of redox-state and energy metabolism fluctuations with time (∼6 h) are observed, where ROS/GSH levels rebound to a maximum peak (up to ∼280%) higher than the normal redox state after hitting the bottom within a short time (1 h). Notably, systematically triggered redox stress response can sensitize cells to an extremely endangered metastable state. The synergy of temporally photoactivated thermal stress can produce overwhelming oxidative stress, thus leading to significant inhibition of cancer cells. This work established a new paradigm of redox perturbator-based programed and combined cancer therapy.

Photothermally triggered melting and perfusion: responsive colloidosomes for cytosolic delivery of membrane-impermeable drugs in tumor therapy.

A cell membrane barrier which dominates the therapeutic efficacy and systemic side effects is a major bottleneck in the field of drug delivery. Herein, a therapeutic system capable of photothermally triggered on-demand and cytosolic delivery was achieved by polydopamine (PDA) nanoparticle-stabilized colloidosomes. An organic phase change material (PCM, saturated fatty acids) was employed as the lipid core for Pickering emulsification and drug encapsulation, and arginine was utilized as a linker to induce the directional interactions between nanoemulsion droplets and heterogeneously nucleated PDA nanoparticles. Moreover, the PDA particle stabilizers concomitantly mediated the grafting of hydrophilic polymer PEG to further improve dispersibility. The resultant colloidosomes after cooling possess lowered melting points and superior dispersion stability over 7 days. When irradiated with near-infrared light (808 nm), sequential processes of fatty acid melting and direct drug perfusion into the cytosol took place within 10 min. The employment of vorinostat (SAHA, histone deacetylase inhibitor) as a model membrane-impermeable drug resulted in remarkable enhancement of anti-cancer effects both in vitro (5.2 fold reduction in IC50) and in vivo (7.3 fold increase in tumor inhibition rate) with respect to the free drug. The remotely triggered transformable nanoplatform paves a new avenue of responsive and efficient cytosolic perfusion to overcome biological membrane barriers on the basis of colloidosomes.

Redox Host-Guest Nanosensors Installed with DNA Gatekeepers for Immobilization-Free and Ratiometric Electrochemical Detection of miRNA.

Electrochemical nanosensors by integrating functional nucleic acids and nanomaterials hold a great promise in the fast detection of biomarkers, yet the current systems possess limitations on the accessibility of target-probe and probe-electrode interactions and the repeatability of detection. Herein, a host-guest assembly strategy is developed to build redox nanosensors for an immobilization-free and ratiometric electrochemical detection system. Specifically, electroactive molecule (Em ) guests are loaded in porous hosts of polydopamine nanoparticles (MPDA) to act as dual-signal redox reporters. Hybrid DNA probes of G-quadruplex and a single-stranded anchor DNA are installed as gatekeepers for sealing the mesopores. Thereby, miRNA triggered Em release by strand displacement reactions and the homogeneous transportation of the hosts/guests to the electrode facilitate the generation of reference signal/response signal at different potentials. Concomitantly applied NIR irradiation boosts the electron transfer from MPDA to the electrode and results in a tenfold increase in the reference signal. Finally, the sensing system through the differential pulse voltammetry method achieves a highly repeatable detection (relative standard deviation 3.8%) of miRNA with a lower detection limit (362 × 10-15 m). This attractive system paves the way for rational designs of advanced electrochemical biosensors and smart diagnosis.

Interface-Hybridization-Enhanced Photothermal Performance of Polypyrrole/Polydopamine Heterojunctions on Porous Nanoparticles.

Photothermal conversion agents (PTCAs) based on π-conjugated polymers are promising for cancer therapy, but the alteration of bandgap energies toward boosted photothermal properties remains challenging. Herein, polymer PTCAs with heterojunctions of a binary optical component are developed by interface hybridization on porous particles. Specifically, polypyrrole (PPy) nanodomains are successfully hosted on the wet-adhesive surface of mesoporous polydopamine nanoparticles through the loading and polymerization of pyrrole in the confined pore space (≈5.0 nm). The near-infrared absorbing polymers in the heterojunctions possess similar five-membered heterocyclic rings and can interact mutually to generate photoinduced electron transfer (PET). Such a large-area optoelectronic interaction progressively reduces the bandgap energy (down to 0.56 eV) by increasing the doped amount of PPy, which consequently enhances the extinction coefficient and photothermal conversion efficiency by 4.6- and 2.2-fold, respectively. Notably, the hybrid PTCA exhibits good biocompatibility, photocytotoxicity, and great potential for cancer therapy.