Biomimetic Lung-Targeting Nanoparticles with Antioxidative and Nrf2 Activating Properties for Treating Ischemia/Reperfusion-Induced Acute Lung Injury.

Ischemia/reperfusion (IR)-induced acute lung injury (ALI) has a high mortality rate. Reactive oxygen species (ROS) play a crucial role in causing cellular damage and death in IR-induced ALI. In this work, we developed a biomimetic lung-targeting nanoparticle (PC@MB) as an antioxidative lung protector for treating IR-induced ALI. PC@MBs showed excellent ROS scavenging and Nrf2 activation properties, along with a lung-targeting function through autologous cell membrane coating. The PC@MBs exhibited an impressive antioxidative and pulmonary protective role via redox homeostasis recovery through Nrf2 and heme oxygenase-1 activation. PC@MBs could maintain cell viability by effectively scavenging the intracellular ROS and restoring the redox equilibrium in the lesion. In the IR mouse model, the PC@MBs preferentially accumulated in the lung and distinctly repaired the pneumonic damage. Our strategy has the potential to offer a promising therapeutic paradigm for treating IR-induced ALI through the incorporation of different therapeutic mechanisms.

Uncovering the Fate and Risks of Intravenously Injected Prussian Blue Nanoparticles in mice by an Integrated Methodology of Toxicology, Pharmacokinetics, Proteomics, and Metabolomics.

BACKGROUND: Prussian blue (PB) nanoparticles (NPs) have been intensively investigated for medical applications, but an in-depth toxicological investigation of PB NPs has not been implemented. In the present study, a comprehensive investigation of the fate and risks of PB NPs after intravenous administration was carried out by using a mouse model and an integrated methodology of pharmacokinetics, toxicology, proteomics, and metabolomics. RESULTS: General toxicological studies demonstrated that intravenous administration of PB NPs at 5 or 10 mg/kg could not induce obvious toxicity in mice, while mice treated with a relatively high dose of PB NPs at 20 mg/kg exhibited loss of appetite and weight decrease in the first two days postinjection. Pharmacokinetic studies revealed that intravenously administered PB NPs (20 mg/kg) underwent fast clearance from blood, highly accumulated in the liver and lungs of mice, and finally cleared from tissues. By further integrated proteomics and metabolomics analysis, we found that protein expression and metabolite levels changed significantly in the liver and lungs of mice due to the high accumulation of PB NPs, leading to slight inflammatory responses and intracellular oxidative stress. CONCLUSIONS: Collectively, our integrated experimental data imply that the high accumulation of PB NPs may cause potential risks to the liver and lungs of mice, which will provide detailed references and guidance for further clinical application of PB NPs in the future.

Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.

BACKGROUND: Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. RESULTS: In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. CONCLUSION: These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.

Removal of Di-n-butyl phthalate from aged leachate under optimal hydraulic condition of leachate treatment process and in the presence of its dominant bacterial strains.

The effects of hydraulic condition of reactor and the dominant degrading bacteria on the removal of di-n-butyl phthalate (DBP) from aged landfill leachate by anaerobic/anoxic/oxic (A/A/O) leachate treatment process were investigated. The optimal DBP removal (96.0%) was obtained from aged leachate when the hydraulic retention time (HRT) of the reactor was 3 d, internal reflux ratio of the reactor was 200%, and external reflux ratio of the reactor was 60%, respectively. The removal efficiency of DBP was significantly improved after the inoculation of the dominant DBP-degrading bacteria (Pseudomonas sp. W1) in the reactor. The mean removal efficiencies of DBP before and after inoculation were 94.1% and 97.7%, respectively. Furthermore, the inoculation of dominant DBP-degrading bacteria changed the original sludge structure and characteristics, which was more conducive to the removal of DBP. These results provide theoretical basis for the effective removal of DBP from aged leachate by the biological treatment process.

Porphyrin-Based Nanomedicines for Cancer Treatment.

As unique molecules with both therapeutic and diagnostic properties, porphyrin derivatives have been extensively employed for cancer treatment. Porphyrins not only show powerful phototherapeutic effects (photodynamic and photothermal therapies), but also exhibit excellent imaging capacities, such as near-infrared fluorescent imaging (NIRFI), magnetic resonance imaging (MRI), photoacoustic imaging (PAI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). In order to take advantage of their robust phototherapeutic effects and excellent imaging capacities, porphyrins can be used to create nanomedicines with effective therapeutic and precise diagnostic properties for cancer treatment. In this Review, we summarize porphyrin-based nanomedicines which have been developed recently, including porphyrin-based liposomes, micelles, polymeric nanoparticles, peptide nanoparticles, and small-molecule nanoassemblies, and their applications on cancer therapy and diagnosis. The outlook and limitation of porphyrin-based nanomedicines are also reviewed.

Novel redox-responsive polymeric magnetosomes with tunable magnetic resonance property for in vivo drug release visualization and dual-modal cancer therapy.

Monitoring of in vivo drug release from nan by non-invasive approaches Remains very challenging. Herein we report on novel redox-responsive polymeric magnetosomes (PolyMags) with tunable magnetic resonance imaging (MRI) properties for in vivo drug release monitoring and effective dual-modal cancer therapy. The encapsulation of doxorubicin (DOX) significantly decreased PolyMags' T2 contrast enhancement and transverse relaxation rate R2, depending on the drug loading level. The T2 enhancement and R2 could be recovered once the drug was released upon PolyMags' disassembly. T2 & T2* MRI and diffusion-weighted imaging (DWI) were utilized to quantitatively study the correlation between MRI signal changes and drug release, and discover the MR tuning mechanisms. We visualized the in vivo drug release pattern based on such tunable MRI capability via monitoring the changes in T2-weighted images, T2 & T2* maps and R2 & R2* values. Interestingly, the PolyMags possessed excellent photothermal effect, which could be further enhanced upon DOX loading. The PolyMags were highly efficacious to treat breast tumors on xenograft model with tumor-targeted photothermal-and chemo-therapy, achieving a complete cure rate of 66.7%. The concept reported here is generally applicable to other micellar and liposomal systems for image-guided drug delivery & release applications toward precision cancer therapy.

Zinc Oxide Nanoparticles as Adjuvant To Facilitate Doxorubicin Intracellular Accumulation and Visualize pH-Responsive Release for Overcoming Drug Resistance.

Multidrug resistance (MDR) of cancer is a challenge to effective chemotherapeutic interventions. The stimulus-responsive drug delivery system (DDS) based on nanotechnology provides a promising approach to overcome MDR. Through the development of a doxorubicin delivery system based on zinc oxide nanomaterials, we have demonstrated that MDR in breast cancer cell line can be significantly circumvented by a combination of efficient cellular uptake and a pH-triggered rapid drug release due to degradation of nanocarriers in acidic environment. Doxorubicin and zinc oxide nanoparticles, compared with free doxorubicin, effectively enhanced the intracellular drug concentration by simultaneously increasing cell uptake and decreasing cell efflux in MDR cancer cells. The acidic environment-triggered release of drug can be tracked real-time by the doxorubicin fluorescence recovery from its quenched state. Therefore, with the combination of therapeutic potential and the capacity to track release of drug in cancer cells, our system holds great potential in nanomedicine by serving dual roles of overcoming drug resistance and tracking intracellular drug release from the DDS.

Synergistically Enhanced Therapeutic Effect of a Carrier-Free HCPT/DOX Nanodrug on Breast Cancer Cells through Improved Cellular Drug Accumulation.

We are interested in developing systems for simultaneous delivery of two or more chemotherapeutic agents. Simple physical mixing of drugs may reduce the therapeutic effect and cause unexpected or even dangerous side-effects. For example, when 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) injection solutions are mixed, the curative effect is actually reduced in clinical practice. In this study we demonstrated that when HCPT and DOX are combined into a single nanoparticle, their toxicity to tumor cells in vitro is synergistically enhanced. We used a simple and "green" reprecipitation method to successfully create a carrier-free dual-drug delivery system by self-nanocrystallization of the drug molecules. When HCPT and DOX were coassembled, they formed small, spherical nanodrug particles with a positive surface charge. Cellular uptake of HCPT was improved and nuclear accumulation increased as much as 1.57-fold in comparison to HCPT alone. The carrier-free HCPT/DOX nanoparticles demonstrated enhanced synergistic cytotoxicity against breast cancer cells in vitro, while an antagonistic effect was observed when HCPT and DOX were directly mixed at high concentration.

A fluorescent probe with restricted intramolecular rotation-induced emission for label-free detection of mercury ions.

Formation of T-Hg(2+)-T complexes changes the configuration of a single-stranded DNA, leading to enhanced fluorescence of an anchored cyanine-based probe that displays restricted intramolecular rotation (RIR)-induced emission. This label-free system can be used as a sensor for mercury ions with a detection limit of 4 nM.

Structural design of microfluidic channels for blood plasma separation.

Microfluidics devices for separation of plasma from whole blood can be applied to numerous clinical laboratory and point-of-care diagnostics, since over 90% of blood diagnosis tests are conducted using plasma. This paper proposed a structural design of microfluidic channels for blood plasma separation. The Euler-Euler Laminar Flow Model in COMSOL Multiphysics has been utilized to simulate the blood flow behavior in microchannels. Micro chips with separating microchannels of different designs were fabricated and tested. The geometrical effect of microchannels on plasma separation was investigated. Simulation results show that curved channel contributes little in lateral migration of cells in low flow rate and becomes a difficult choice in the case of high flow rate due to the coupling of centrifugal migration and Dean Vortex. Studies on the bifurcation corner radius and the angle between main channel and side channel show that an abrupt change in flow direction of cell free layer helps to get more plasma with higher purity. An optimal design of multi-bifurcation separator has been achieved by balancing the flow resistances of the side channels and the main channels.

Functionalized nanoscale micelles improve drug delivery for cancer therapy in vitro and in vivo.

Poor penetration of therapeutic drugs into tumors is a major challenge in anticancer therapy, especially in solid tumors, leading to reduced therapeutic efficacy in vivo. In the study, we used a new tumor-penetrating peptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulated nanoscale micelles. The CRGDK peptide triggered specific binding to neuropilin-1, leading to enhanced cellular uptake and cytotoxicity in vitro and highly accumulation and penetration in the tumors in vivo.

A metal-coordination stabilized small-molecule nanomedicine with high drug-loading capacity and synergistic photochemotherapy for cancer treatment.

Conventional nanomedicines typically employ a significant amount of excipients as carriers for therapeutic delivery, resulting in generally low drug-loading and compromised anti-cancer efficacy. Here, we propose a small-molecule nanomedicine (CMC NP) directly assembled using a chemotherapeutic drug (chlorambucil, CBL) and a phototherapeutic agent (chlorin e6, Ce6), and stabilized by metal coordination. The CMC NP exhibits exceptionally high drug loading (89.21%), robust stability, and smart disassembly in response to glutathione (GSH). Such a straightforward yet multifunctional delivery strategy could be a better alternative to overcome the above shortcomings of conventional nanomedicines while achieving enhanced efficacy. The CMC NP not only directly induces CBL-induced chemotherapy but also elicits synergistic antitumor responses through Ce6-mediated photodynamic and photothermal therapies. Owing to the multifaceted efforts from photodynamic, photothermal and chemo-therapies, the CMC NP exhibits excellent antitumor efficacy with negligible systemic toxicity which is untenable in traditional CBL-induced chemotherapy. Therefore, this study provides a feasible strategy for overcoming existing challenges and presents a potential opportunity to augment the clinical therapeutic effectiveness associated with conventional nanomedicine.

Biomimetic Nanomodulator Regulates Oxidative and Inflammatory Stresses to Treat Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a devastating complication of sepsis, affecting approximately 70% of patients with sepsis in intensive care units (ICU). Although the pathophysiological mechanisms remain elusive, sepsis is typically accompanied by systemic inflammatory response syndrome (SIRS) and hyper-oxidative conditions. Here, we introduce a biomimetic nanomodulator (mAOI NP) that specifically targets inflammation site and simultaneously regulates oxidative and inflammatory stresses. mAOI NPs are constructed using metal-coordinated polyphenolic antioxidants (tannic acid) and flavonoid quercetin, which are then coated with macrophage membrane to enhance pharmacokinetics and enable SAE targeting. In a cecal ligation and puncture (CLP)-induced severe sepsis model, mAOI NPs effectively mitigate oxidative stress by purging reactive oxygen species, repairing mitochondrial damage and activating the Nrf2/HO-1 signaling pathway; while polarizing M1 macrophages or microglia toward anti-inflammatory M2 subtype. mAOI NPs potently inhibit sepsis progress, prolong overall survival from 25 to 66% and enhance learning and memory capabilities in SAE mice. Further proteomics analysis reveals that mAOI NPs modulate neurodevelopment processes related to learning and memory formation while also exerting anti-inflammatory and antioxidative effects on brain tissue responses associated with SAE pathology. This study offers significant potential for improving patient outcomes and revolutionizing the treatment landscape for this devastating complication of sepsis.

Stress response mechanism of wastewater biological nitrogen removal systems to environmentally realistic concentrations of tire wear particles: Contribution of leachable additives.

The study quantified the biological nitrogen removal performance, microbial metabolism, microbial community structure, and antioxidant system in a sequencing batch reactor under long-term exposure to 0.1 and 1 mg/L tire wear particles (TWPs), and determined the contribution of leachable additives to the biotoxicity of TWPs. The results showed that long-term exposure to 0.1 and 1 mg/L TWPs inhibited both the nitrification and denitrification processes, reducing ammonia nitrogen (NH4+-N) and total nitrogen (TN) removal efficiency. The TWP leachate (TWPL) primarily contributed to the denitrification inhibition by TWPs, potentially due to the high concentration of zinc ions in the leachable additive. Furthermore, both TWP and TWPL inhibit nitrogen conversion, with TWP inhibiting the generation and transfer of electrons, while TWPL only negatively affects the electron transfer process. This study presents novel insights into the impact of TWPs on biological nitrogen removal, underscoring its broader implications for the geochemical nitrogen cycle.

Interface engineering of Mo-doped Ni9S8/Ni3S2 multiphase heterostructure nanoflowers by one step synthesis for efficient overall water splitting.

Accelerating charge transfer efficiency by constructing heterogeneous interfaces on metal-based substrates is an effective way to improve the electrocatalytic performance of materials. However, minimizing the substrate-catalyst interfacial resistance to maximize catalytic activity remains a challenge. This study reports a simple interface engineering strategy for constructing Mo-Ni9S8/Ni3S2 heterostructured nanoflowers. Experimental and theoretical investigations reveal that the primary role assumed by Ni3S2 in Mo-Ni9S8/Ni3S2 heterostructure is to replace nickel foam (NF) substrate for electron conduction, and Ni3S2 has a lower potential energy barrier (0.76 to 1.11 eV) than NF (1.87 eV), resulting in a more effortless electron transfer. The interface between Ni3S2 and Mo-Ni9S8 effectively regulates electron redistribution, and when the electrons from Ni3S2 are transferred to Mo-Ni9S8, the potential energy barriers at the heterogeneous interface are 1.06 eV, lower than that between NF and Ni3S2 (1.53 eV). Mo-Ni9S8/Ni3S2-0.1 exhibited excellent oxygen evolution reaction (OER)/hydrogen evolution reaction (HER) bifunctional catalytic activity in 1 M KOH, with overpotentials of only 223 mV@100 mA cm-2 for OER and 116 mV@10 mA cm-2 for HER. Moreover, when combined with an alkaline electrolytic cell, it required only an ultra-low cell voltage of 1.51 V to drive a current density of 10 mA cm-2. This work provides new inspirations for rationally designing interface engineering for advanced catalytic materials.

A supramolecular assembly strategy for hydrophilic drug delivery towards synergistic cancer treatment.

To improve the drug loading, tumor targeting, and delivery simplicity of hydrophilic drugs, we propose a supramolecular assembly strategy that potentially benefits a wide range of hydrophilic drug delivery. Firstly, we choose a hydrophilic drug (tirapazamine) as a model drug to directly co-assemble with chlorin e6 (Ce6) at different molar ratios, and systematically evaluate the resultant Ce6-tirapazamine nanoparticles (CT NPs) in aspects of size distribution, polydispersity, morphology, optical properties and molecular dynamics simulation. Based on the assembling facts between Ce6 and tirapazamine, we summarize a plausible rule of the supramolecular assembly for hydrophilic drugs. To validate our findings, more drugs with increasing hydrophilicity, such as temozolomide, gemcitabine hydrochloride and 5-azacytidine, successfully co-assemble with Ce6 into nanostructures by following similar assembling behaviors, demonstrating that our assembling rule may guide a wide range of hydrophilic drug delivery. Next, the combination of Ce6 and tirapazamine was chosen as the representative to investigate the anti-tumor activities of the supramolecular assemblies. CT NPs showed synergistic anti-tumor efficacy, increased tumor accumulation and significant tumor progression and metastasis inhibition in tumor-bearing mice. We anticipate that the supramolecular assembly mechanism will provide broad guidance for developing easy-to-make but functional nanomedicines. STATEMENT OF SIGNIFICANCE: Although thousands of nanomedicines have been developed, only a few have been approved for clinical use. The manufacturing complexity significantly hinders the "bench-to-bed" translation of nanomedicines. Hence, we need to rethink how to conduct research on translational nanomedicines by avoiding more and more complex chemistry and complicated nanostructures. Here, we summarize a plausible rule according to multiple supramolecular assembly pairs and propose a supramolecular assembly strategy that can improve the drug loading, tumor targeting, and manufacturing simplicity of nanomedicine for hydrophilic drugs. The supramolecular assembly strategy would guide a broader range of drug delivery to provide a new paradigm for developing easy-to-make but multifunctional nanoformulations for synergistic cancer treatment.

Drug-drug conjugates self-assembled nanomedicines triggered photo-/immuno- therapy for synergistic cancer treatments.

Although immunotherapies have made progress in cancer treatment, their clinical response rates vary widely and are typically low due to sparse immune cell infiltration (immune "cold") and suppressive tumor immune microenvironment (TIME). A simple yet effective approach that integrates a variety of immune-stimulating and TIME-modulating functions could potentially address this clinical challenge. Herein, we conjugate two small molecules, including a photosensitizer (pyropheophorbide-a, PA) and a Toll-like receptor 7/8 agonist (resiquimod, R848), into prodrug (PA-R848) that self-assembles into PA-R848 esterase responsive nanoparticles (PARE NPs) with 100% drug composition and synergistic photo-/immune- therapeutic effects. In PARE NPs, PA exhibits strong phototherapeutic effects which ablate the primary tumor directly and elicits immunogenic cell death (ICD) to promote the immune response. R848 effectively polarizes the M2-type tumor-associated macrophage (TAM) to M1-type TAM, consequently reversing the "cold" and suppressive TIME when working together with phototherapy. The PARE NPs can efficiently pare down the tumor development by two synergisms, including i) synergistic immunotherapy between ICD and TAM polarization; ii) and the antitumor effects between phototherapy and immunotherapy. On a head-neck squamous cell carcinoma mouse model, PARE NPs combined with PD-1 antibody eliminate primary tumors, and significantly inhibit the progress of distant tumors thanks to the robust antitumor immunity enhanced by the PARE NPs.

A transformable nanoplatform with multiple therapeutic and immunostimulatory properties for treatment of advanced cancers.

Cancer is a complex pathological phenomenon that needs to be treated from different aspects. Herein, we developed a size/charge dually transformable nanoplatform (PDR NP) with multiple therapeutic and immunostimulatory properties to effectively treat advanced cancers. The PDR NPs exhibit three different therapeutic modalities (chemotherapy, phototherapy and immunotherapy) that can be used to effectively treat primary and distant tumors, and reduce recurrent tumors; the immunotherapy is simultaneously activated by three major pathways, including toll-like receptor, stimulator of interferon genes and immunogenic cell death, effectively suppresses the tumor development in combination with an immune checkpoint inhibitor. In addition, PDR NPs show size and charge responsive transformability in the tumor microenvironment, which overcomes various biological barriers and efficiently delivers the payloads into tumor cells. Taking these unique characteristics together, PDR NPs effectively ablate primary tumors, activate strong anti-tumor immunity to suppress distant tumors and reduce tumor recurrence in bladder tumor-bearing mice. Our versatile nanoplatform shows great potential for multimodal treatments against metastatic cancers.

Integrating electronic structure regulation and dynamic active sites construction on NixCd1-xS-Ni0 photocatalyst for efficient hydrogen evolution.

Regulating electronic structure and enriching active sites of photocatalysts are effective strategies to promote hydrogen evolution. Herein, a unique NixCd1-xS-Ni0 photocatalyst, including the surface nickel (Ni) doping and atomic Ni0 anchoring sites, is successfully prepared by Ni2+ ions exchange reaction (Ni2++ CdS â†’ NixCd1-xS) and in-situ photo-induction of Ni0(Ni2++NixCd1-xS→hνNixCd1-xS-Ni0), respectively. As to Ni doping, the Ni replaced cadmium (Cd) atoms introduce hybridized states around the Fermi level, modulating the electronic structure of adjacent S atoms and optimizing the photocatalytic activity of sulfur (S) atoms. Besides, photogenerated Ni0 atoms, anchored on unsaturated S atoms, act as charge transfer bridges to reduce Ni2+ ions in the solution to Ni clusters (NixCd1-xS-Ni0→ne-NixCd1-xS-Ni). Subsequently, the displacement reaction of Ni clusters with protons (H+) spontaneously proceeds to produce hydrogen (H2) in an acidic solution (NixCd1-xS-Ni→2H+H2↑+Ni2++NixCd1-xS-Ni0). The equilibrium of photo-deposition/dissolution of Ni clusters realizes the construction of dynamic active sites, providing sustainable reaction centers and enhancing surface redox kinetics. The NixCd1-xS-Ni0 exhibits a high hydrogen evolution rate of 428 mmol·h-1·g-1 with a quantum efficiency of 75.6 % at 420 nm. This work provides the optimal S electronic structure for photocatalytic H2 evolution and constructs dynamic Ni clusters for chemical replacement reaction. This work provides the optimal S electronic structure for photocatalytic H2 evolution and constructs dynamic Ni clusters for displacement reaction, opening a dual pathway for efficient water reduction.

Programmed-response cross-linked nanocarrier for multidrug-resistant ovarian cancer treatment.

The application of numerous chemotherapeutic drugs has been limited due to poor solubility, adverse side effects, and even multidrug resistance in patients. Polymeric micelles with reversibly cross-linked structures provide a promising solution to these issues. Herein, we optimized and synthesized programable-released disulfide cross-linked micelle (PDCM) based on our previous well-defined dendrimers to deliver the antitumor drug betulinic acid (BA) and paclitaxel (PDCM@PTX) and evaluated the therapeutic efficacy of multidrug-resistant (MDR) simulative orthotopic intraperitoneal ovarian cancer mice models. Comprehensive results demonstrated that PDCM@PTX formed stable nanoparticles able to improve the pharmacokinetic profile and circulation time of PTX, allowing for increased tumor penetration. Furthermore, in the tumor microenvironment, the programable-switches (ester bonds and disulfide cross-linking) of PDCM@PTX were cleaved by the high concentration of glutathione (tumor microenvironment) and esterase (intracellular) present in the tumor, allowing for in situ release of PTX and BA, resulting in intensive therapeutic efficacy in MDR ovarian cancer.