The Convergence of Sonodynamic Therapy and Cuproptosis in the Dual-Responsive Biomimetic CytoNano for Precision Mitochondrial Intervention in Cancer Treatment.

The integration of sonodynamic therapy (SDT) with cuproptosis for targeted cancer treatment epitomizes a significant advancement in oncology. Herein, we present a dual-responsive therapeutic system, "CytoNano", which combines a cationic liposome infused with copper-nitride nanoparticles and oxygen-rich perfluorocarbon (Lip@Cu3N/PFC-O2), all enveloped in a biomimetic coating of neutrophil membrane and acid-responsive carboxymethylcellulose. CytoNano leverages the cellular mimicry of neutrophils and acid-responsive materials, enabling precise targeting of tumors and their acidic microenvironment. This strategic design facilitates the targeted release of Lip@Cu3N/PFC-O2 within the tumor, enhancing cancer cell uptake and mitochondrial localization. Consequently, it amplifies the therapeutic efficacy of both Cu3N-driven SDT and cuproptosis while preserving healthy tissues. Additionally, CytoNano's ultrasound responsiveness enhances intratumoral oxygenation, overcoming physiological barriers and initiating a combined sonodynamic-cuproptotic effect that induces multiple cell death pathways. Thus, we pioneer a biomimetic approach in precise sonodynamic cuproptosis, revolutionizing cancer therapy.

Dual-Responsive MnO2-Loaded Carbonaceous Nanobottle Motors Fabricated by Interfacial Superassembly for On-The-Fly MicroRNA Sensing.

Diverse nanomotors with advanced motion manipulation have been proposed to revolutionize the way problems in many fields are solved. However, rational and controllable synthetic methods of multifunctional nanomotor are still limited. Herein, dual-responsive MnO2-loaded carbonaceous nanobottle motors (MnO2 NBMs) are developed through an interfacial superassembly strategy. Asymmetric carbonaceous nanobottles are first synthesized, and the reductive carbonaceous shell induces an oxidation-reduction reaction with KMnO4 for in-situ growth of MnO2 nanosheets, which enables the nanomotor to perform either self-diffusiophoretic or self-thermophoretic motion in response to H2O2 and near-infrared light, respectively. Inspired by bioaffinity sensing, the nanomotors are sequentially assembled with functional nanoparticles and hairpin DNA to construct swimming functional MnO2 NBMs (MnO2 FNBMs) probes. The probes can move around complex samples to improve target miRNA transport and accelerate receptor-target interaction. Coupling with the photocurrent-signal amplification, the self-assembly of photoelectrochemical (PEC) biosensors has been achieved for sensitive microRNA detection. Trace amounts of miRNA-155 can be quickly detected with a wide detection range (100 fM to 100 nM). Moreover, the direct detection of microRNA in tumor cell lysates by the biosensor is demonstrated. Given the merits of automation and miniaturization, the proposed strategy provides a promising method for fast and effective self-assembly of biosensors.

Dual pH and Ca2+-Responsive PEG-Modified Pillar[5]arene-Based Supramolecular Nanodrug Delivery System: Excellent Cargo Encapsulation and Minimal Drug Toxicity.

Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca2+-responsive pillar[5]arene-based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG-modified pillar[5]arene and the bipyridilium salt derivative EV through simple host-guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6 %. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half-life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212 % and 179 %, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host-guest drug delivery system.

In situ growth of dual-responsive polymer as coating for open tubular capillary electrochromatographic separation of epimedins.

Recently, open tubular capillary electrochromatography (OT-CEC) has captured considerable interest; its efficient separation capability hinges on the interactions between analytes and polymer coatings. However, in situ growth of stimuli-responsive polymers as coatings has been rarely studied and is crucial for expanding the OT-CEC technique and its application. Herein, following poly(styrene-maleicanhydride) (PSM) chemically bonded onto the inner surface of the capillary, a dual pH/temperature stimuli-responsive block copolymer, P(SMN-COOH), was prepared by in situ polymerizing poly(N-isopropylacrylamide) carboxylic acid terminated [P(N-COOH)] in PSM. An OT-CEC protocol was first explored using the coated capillary for epimedins separation. As a proof of concept, the developed OT-CEC system facilitated hydrogen bonding and tuning the hydrophilic/hydrophobic interactions between the test analytes and the P(SMN-COOH) coating by varying buffer pH and environmental temperature. Four epimedins with similar chemical structures were baseline separated under 40 °C at pH 10.0, exhibiting dramatical improvement in separation efficiency in comparison to its performance under 25 °C at pH 4.0. In addition, the coated capillary showed good repeatability and reusability with relative standard deviations for migration time and peak area between 0.7 and 1.7% and between 2.9 and 4.6%, respectively, and no significant changes after six runs. This work introduces a paradigm for efficient OT-CEC separation of herbal medicines through adjusting the interactions between analytes and smart polymer coatings, addressing polymer coating design and OT-CEC challenges.

Surface Topology of Redox- and Thermoresponsive Nanogel Droplets.

Hydrogels are usually depicted as a homogenous polymer block with a distinct surface. While defects in the polymer structure are looked into frequently, structural irregularities on the hydrogel surface are often neglected. In this work, thin hydrogel layers of ≈100 nm thickness (nanogels) are synthesized and characterized for their structural irregularities, as they represent the surface of macrogels. The nanogels contain a main-chain responsiveness (thermo responsive) and a responsiveness in the cross-linking points (redox responsive). By combining data from ellipsometry using box-model and two-segment-model analysis, as well as atomic force microscopy, a more defined model of the nanogel surface can be developed. Starting with a more densely cross-linked network at the silica wafer surface, the density of cross-linking gradually decreases toward the hydrogel-solvent interface. Thermo-responsive behavior of the main chain affects the entire network equally as all chain segments change solubility. Cross-linker-based redox-responsiveness, on the other hand, is only governed by the inner, more cross-linked layers of the network. Such dual responsive nanogels hence allow for developing a more detailed model of a hydrogel surface from free radical polymerization. It provides a better understanding of structural defects in hydrogels and how they are affected by responsive functionalities.

pH/GSH dual-responsive nanoparticle for auto-amplified tumor therapy of breast cancer.

Breast cancer remains a malignancy that poses a serious threat to human health worldwide. Chemotherapy is one of the most widely effective cancer treatments in clinical practice, but it has some drawbacks such as poor targeting, high toxicity, numerous side effects, and susceptibility to drug resistance. For auto-amplified tumor therapy, a nanoparticle designated GDTF is prepared by wrapping gambogic acid (GA)-loaded dendritic porous silica nanoparticles (DPSNs) with a tannic acid (TA)-Fe(III) coating layer. GDTF possesses the properties of near-infrared (NIR)-enhanced and pH/glutathione (GSH) dual-responsive drug release, photothermal conversion, GSH depletion and hydroxyl radical (·OH) production. When GDTF is exposed to NIR laser irradiation, it can effectively inhibit cell proliferation and tumor growth both in vitro and in vivo with limited toxicity. This may be due to the synergistic effect of enhanced tumor accumulation, and elevated reactive oxygen species (ROS) production, GSH depletion, and TrxR activity reduction. This study highlights the enormous potential of auto-amplified tumor therapy.

Macrocyclic Dual-Locked "Turn-On" Drug for Selective and Traceless Release in Cancer Cells.

Drug safety and efficacy due to premature release into the bloodstream and poor biodistribution remains a problem despite seminal advances in this area. To circumvent these limitations, we report drug cyclization based on dynamic covalent linkages to devise a dual lock for the small-molecule anticancer drug, camptothecin (CPT). Drug activity is "locked" within the cyclic structure by the redox responsive disulfide and pH-responsive boronic acid-salicylhydroxamate and turns on only in the presence of acidic pH, reactive oxygen species and glutathione through traceless release. Notably, the dual-responsive CPT is more active (100-fold) than the non-cleavable (permanently closed) analogue. We further include a bioorthogonal handle in the backbone for functionalization to generate cyclic-locked, cell-targeting peptide- and protein-CPTs, for targeted delivery of the drug and traceless release in triple negative metastatic breast cancer cells to inhibit cell growth at low nanomolar concentrations.

Magnetically and Electrically Responsive Soft Actuator Derived from Ferromagnetic Bimetallic Organic Framework.

The advancement in smart devices and soft robotics necessitates the use of multiresponsive soft actuators with high actuation stroke and stable reversibility for their use in real-world applications. Here, this work reports a magnetically and electrically dual responsive soft actuator based on neodymium and iron bimetallic organic frameworks (NdFeMOFs@700). The ferromagnetic NdFeMOFs@700 exhibits a porous carbon structure with excellent magnetization saturation (166.96 emu g-1 ) which allows its application to a dual functional material in both magnetoactive and electro-ionic actuations. The electro-ionic soft actuator, which is fabricated using NdFeMOFs@700 and PEDOT-PSS, demonstrates 4.5 times higher ionic charge storage capacity (68.21 mF cm-2 ) and has excellent cycle stability compared with the PEDOT-PSS based actuator. Under a low sinusoidal input voltage of 1 V, the dual-responsive actuator displays bending displacement of 15.46 mm and also generates deflection of 10 mm at 50 mT. Present results show that the ferromagnetic bimetallic organic frameworks can open a new way to make dual responsive soft actuators due to the hierarchically porous structures with its high redox activity, superior magnetic properties, and larger electrochemical capacitance. With the NdFeMOFs@700 based soft actuators, walking movement of a starfish robot is demonstrated by applying both the magnetic and electric fields.

Dual-responsive nanoparticles loading bevacizumab and gefitinib for molecular targeted therapy against non-small cell lung cancer.

The combination of vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKIs) is newly available for molecular targeted therapy against non-small cell lung cancer (NSCLC) in clinic. However, the therapeutic benefits remain unsatisfying due to the poor drug delivery to targets of interest. In this study, we developed bevacizumab-coated gefitinib-loaded nanoparticles (BCGN) with dual-responsive drug release for inhibiting tumor angiogenesis and phosphorylation of epidermal growth factor receptor (EGFR). Through an exogenous corona strategy, bevacizumab is easily coated on gefitinib-loaded nanoparticles via electrostatic interaction. After intravenous injection, BCGN are efficiently accumulated in NSCLC tumors as confirmed by dual-model imaging. Bevacizumab is released from BCGN upon oxidation in tumor microenvironment, whereas gefitinib is released after being internalized by tumor cells and disassembled in reduction cytoplasm. The dual-responsive release of bevacizumab and gefitinib significantly inhibits tumor growth in both A549 and HCC827 human NSCLC models. Our approach provides a promising strategy to improve combinational molecular targeted therapy of NSCLC with precisely controlled drug release.

Docetaxel-loaded pH/ROS dual-responsive nanoparticles with self-supplied ROS for inhibiting metastasis and enhancing immunotherapy of breast cancer.

BACKGROUND: Although stimuli-responsive nanoplatforms were developed to deliver immunogenic cell death (ICD) inducers to enhance cancer immunotherapy, the complete release of ICD inducers into the tumor microenvironment (TME) was limited by the inadequate supplementation of endogenous stimulus (e.g., reactive oxygen species (ROS)). To address this issue, we synthesized a self-responsive nanomaterial with self-supplied ROS, which mainly consists of a ROS responsive moiety HPAP and cinnamaldehyde (CA) as the ROS-generating agent. The endogenous ROS can accelerate the degradation of HPAP in materials to release docetaxel (DTX, an ICD inducer). In intracellular acidic environment, the pH-sensitive acetal was cleaved to release CA. The released CA in turn induces the generation of more ROS through mitochondrial damage, resulting in amplified DTX release. Using this self-cycling and self-responsive nanomaterial as a carrier, DTX-loaded pH/ROS dual-responsive nanoparticles (DTX/FA-CA-Oxi-αCD NPs) were fabricated and evaluated in vitro and in vivo. RESULTS: In vitro experiments validated that the NPs could be effectively internalized by FA-overexpressed cells and completely release DTX in acidic and ROS microenvironments to induce ICD effect. These NPs significantly blocked 4T1 cell migration and decreased cell invasion. In vivo experiments demonstrated that the tumor-targeted NPs significantly inhibited tumor growth and blocked tumor metastasis. More importantly, these NPs significantly improved immunotherapy through triggering effector T-cell activation and relieving the immunosuppressive state of the TME. CONCLUSIONS: Our results demonstrated that DTX/FA-CA-Oxi-αCD NPs displayed great potential in preventing tumor metastasis, inhibiting tumor growth, and improving the efficacy of anti-PD-1antibody.

"Dual sensitive supramolecular curcumin nanoparticles" in "advanced yeast particles" mediate macrophage reprogramming, ROS scavenging and inflammation resolution for ulcerative colitis treatment.

Ulcerative colitis (UC) faces some barriers in oral therapy, such as how to safely deliver drugs to the colon and accumulate in the colon lesions. Hence, we report an advanced yeast particles system loaded with supramolecular nanoparticles with ROS scavenger (curcumin) to treat UC by reducing oxidative stress state and inflammatory response and accelerating the reprogramming of macrophages. In this study, the dual-sensitive materials are bonded on ß-cyclodextrin (ß-CD), the D-mannose (Man) is modified to adamantane (ADA), and then loaded with curcumin (CUR), to form a functional supramolecular nano-delivery system (Man-CUR NPs) through the host-guest interaction. To improve gastrointestinal stability and colonic accumulation of Man-CUR NPs, yeast cell wall microparticles (YPs) encapsulated Man-CUR NPs to form Man-CUR NYPs via electrostatic adsorption and vacuum extrusion technologies. As expected, the YPs showed the strong stability in complex gastrointestinal environment. In addition, the Man modified supramolecular nanoparticles demonstrated excellent targeting ability to macrophages in the in vitro cellular uptake study and the pH/ROS sensitive effect of Man-CUR NPs was confirmed by the pH/ROS-dual stimulation evaluation. They also enhanced lipopolysaccharide (LPS)-induced inflammatory model in macrophages through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and scavenging the excess ROS. Notably, in DSS-induced mice colitis model, Man-CUR NYPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways, alleviate oxidative stress by Nrf2/HO-1 signaling pathway, promote macrophages reprogramming and improve the favorable recovery of the damaged colonic tissue. Taken together, this study not only provides strategy for "supramolecular curcumin nanoparticles with pH/ROS sensitive and multistage therapeutic effects" in "advanced yeast particles", but also provided strong theoretical support multi-effect therapy for UC.

A Dual-Responsive Liquid Crystal Elastomer for Multi-Level Encryption and Transient Information Display.

Information security has gained increasing attention in the past decade, leading to the development of advanced materials for anti-counterfeiting, encryption and instantaneous information display. However, it remains challenging to achieve high information security with simple encryption procedures and low-energy stimuli. Herein, a series of strain/temperature-responsive liquid crystal elastomers (LCEs) are developed to achieve dual-modal, multi-level information encryption and real-time, rewritable transient information display. The as-prepared polydomain LCEs can change from an opaque state to a transparent state under strain or temperature stimuli, with the transition strains or temperatures highly dependent on the concentration of long-chain flexible spacers. Information encrypted by different LCE inks can be decrypted under specific strains or temperatures, leading to multi-level protection of information security. Furthermore, with the combination of the phase transition of polydomain LCEs and the photothermal effect of multi-walled carbon nanotubes (MWCNTs), we achieved a repeatable transient information display by using near-infrared (NIR) light as a pen for writing. This study provides new insight into the development of advanced encryption materials with versatility and high security for broad applications.

Electrochemical Actuators with Multicolor Changes and Multidirectional Actuation.

Electrochemical (EC) actuators have garnered significant attention in recent years, yet there are still some critical challenges to limit their application range, such as responsive time, multifunctionality, and actuating direction. Herein, an EC actuator with a back-to-back structure is fabricated by stacking two membranes with bilayer V2 O5 nanowires/single-walled carbon nanotubes (V2 O5 NWs/SWCNTs) networks, and shows a synchronous high actuation amplitude (about ±9.7 mm, ±28.4°) and multiple color changes. In this back-to-back structure, the inactive SWCNTs layer is used as a conductive current collector, and the bilayer network is attached to a porous polymer membrane. The dual-responsive processes of V2 O5 nanowires (V2 O5 NWs) actuation films and actuators are also deeply investigated through in situ EC X-ray diffraction and Raman spectroscopy. The results show that the EC actuation of the V2 O5 NWs/SWCNTs film is highly related to the redox behavior of the pseudocapacitive V2 O5 NWs layer. At last, both V2 O5 NWs and W18 O49 nanowires (W18 O49 NWs)-based EC actuators are constructed to demonstrate the multicolor changes and multidirectional actuation induced by the opposite lattice changes of V2 O5 NWs and W18 O49 NWs during ionic de-/intercalation, guiding the design of multifunctional EC actuators in the future.

Pyrene functionalized oxacalix[4]arene architecture as dual readout sensor for expeditious recognition of cyanide anion.

A pyrene functionalized oxacalix[4]arene architecture (DPOC) was utilized as a fluorescence probe for selective recognition of cyanide ions. The receptor DPOC shows excellent selectivity towards cyanide ion with a red shift of 108 nm in absorption band along with a significant change in colour from light yellow to pink. The fluorescence titration experiments further confirm the lower limit of detection as 1.7µM with no significant influences of competing anions. 1 H-NMR titration experiments support the deprotonation phenomena, as the -NH proton disappears upon successive addition of cyanide ions. The DFT calculation also indicates a certain increment of -NH bond length upon interaction with cyanide ions. The spectral properties as well as colour of DPOC-CN- system may be reversed upon the addition of Ag+/ Cu2+ ions up to 5 consecutive cycles. Moreover, DPOC coated "test strips" were prepared for visual detection of cyanide ions.

Cleanup of oiled shorelines using a dual responsive nanoclay/sodium alginate surface washing agent.

Oil spills may affect ecosystems and endanger public health. In this study, we developed a novel and dual responsive nanoclay/sodium alginate (NS) washing fluid, and systematically evaluated its application potential in oiled shoreline cleanup. The characterization results demonstrated that sodium alginate combined with nanoclay via hydrogen bonds, and was inserted into the interlayer spacing of nanoclay. Adding sodium alginate reduced surface and interfacial tensions, while increasing the viscoelasticity of the washing fluid. Batch experiments were conducted to investigate oil removal performance under various conditions. Additionally, the factorial design analysis showed that three single factors (temperature, oil concentration, and salinity), and two interactive effects (temperature/salinity; and oil concentration/HA) displayed significant effects on the oil removal efficiency of the NS washing fluid. Compared to the commercial surfactants, the NS composite exhibited satisfactory removal efficiencies for treating oily sand. Green materials-stabilized Pickering emulsion can potentially be used for oil/water separation. The NS washing agent displayed excellent pH- and Ca2+- responsiveness, generating transparent supernatants with low oil concentration and turbidity. Our work opens an interesting avenue for designing economical, high performance, and green washing agents.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy.

Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n (P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n (P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n (P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH/ROS dual-responsive GEM/P1 and GEM/P2 micelles have higher cumulative release than single-responsive GEM/P3 and GEM/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.

A "Double-Locked" and Enzyme/pH-Activated Theranostic Agent for Accurate Tumor Imaging and Therapy.

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the "double-locked" strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-ß-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of ß-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first "key") and pH (second "key"), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

Microfluidics-Assisted Engineering of pH/Enzyme Dual-Activatable ZIF@Polymer Nanosystem for Co-Delivery of Proteins and Chemotherapeutics with Enhanced Deep-Tumor Penetration.

The impermeable barriers of solid tumors restrict the co-delivery of protein-based drugs and chemotherapeutics for cancer treatment. Therefore, we developed a ZIF-DOX/RA@DG nanosystem that encapsulates ribonuclease A (RA) and doxorubicin (DOX) in a zeolitic imidazolate framework (ZIF-8) core, with a dextran-based coating (DG). The nanosystem exhibits dual-responsiveness due to γ-glutamyl transpeptidase-activatable cationization and acidic microenvironment-triggered degradation. The DG-coating process was achieved using a microfluidic approach, which stabilized the polymer responsiveness, ZIF-8-based structure, and bioactivity of the encapsulated therapeutics. In vivo results confirmed that the nanosystem could co-deliver RA and DOX to deep impermeable lesions with a synergistic anticancer therapeutic effects. Such a multi-drug delivery system based on an intelligent-responsive design and a microfluidics-assisted synthesis strategy shows great clinical prospects.

Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases.

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle GC-B-Que as an inflammatory-targeted drug, which was comprised by active quercetin (Que) covalently linked to biocompatible glycol chitosan (GC) by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of H2O2, confirming the release of the drug. The in vitro drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 µM H2O2, exhibiting a pH/ROS dual-responsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further in vivo activities and biodistribution experiments found that the GC-B-Que micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by GC-B-Que micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.