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.

Small-molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual-inhibiting properties for bladder cancer treatment.

Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy.

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.

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.

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.

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.

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.

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.

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.

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.

Electrostatic potential-derived charge: a universal OER performance descriptor for MOFs.

Metal-organic frameworks (MOFs) provide opportunities for the design of high-efficiency catalysts attributed to their high compositional and structural tunability. Meanwhile, the huge number of MOFs poses a great challenge to experimental-intensive development of high-performance functional applications. By taking the computationally feasible and structurally representative trigonal prismatic secondary building units (SBUs) of MOFs as the entry point, we introduce a descriptor-based approach for designing high-performance MOFs for the oxygen evolution reaction (OER). The electrostatic potential-derived charge (ESPC) is identified as a robust and universal OER performance descriptor of MOFs, showing a distinct linear relationship with the onset potentials of OER elemental steps. Importantly, we establish an ESPC-based physical pattern of active site-intermediate binding strength, which interprets the rationality of ESPC as an OER performance descriptor. We further reveal that the SBUs with Ni/Cu as active site atoms while Mn/Fe/Co/Ni as spectator atoms have excellent OER activity through the variation pattern of ESPC along with metal composition. The universal correlation between ESPC and OER activity provides a rational rule for designing high-performance MOF-based OER electrocatalysts and can be easily extended to design functional MOFs for a rich variety of catalytic applications.

On-demand targeting nanotheranostics with stimuli-responsive releasing property to improve delivery efficiency to cancer.

Nanocarriers have great potential to enhance drug delivery efficiency and therapeutic effect for various cancers. However, premature drug leakage and non-specific targeting still limit the delivery efficiency. Here, we present a smart on-demand targeting nanotheranostic system (PO-PB@SPIOs) with stimuli-responsive releasing property to improve the delivery efficiency for ovarian cancer. This delivery system prevents premature drug leakage via boronate ester linkages and shields the targeting moieties (phenylboronic acid) from non-specific binding when circulating in the blood. The PO-PB@SPIOs would release the tumor-targeting payload (PB) in response to the tumor microenvironment. Then, PB was able to target the overexpressed sialic acids on tumor cells. The significant improvement of delivery efficiency was demonstrated in vivo by a significantly enhanced signal in near-infrared-fluorescence (NIRF)/magnetic-resonance (MR) imaging (5-fold higher) and a remarkable photo-thermal therapeutic effect (complete cure rate (CCR) up to 80%). Furthermore, due to the on-demand targeting and stimuli-responsive releasing strategy, this nanotheranostic system shows a greater delivery efficiency even than the active-targeting small molecules or control nanoformulations. We believe this delicate design has great potential to develop novel drug nanoformulation.

Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. EXPERIMENTAL DESIGN: SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. RESULTS: PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. CONCLUSIONS: In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

Adsorption characteristics of antibiotics on microplastics: The effect of surface contamination with an anionic surfactant.

Microplastics and antibiotics are common, typical pollutants, and they can cause compound pollution where they coexist in the environment. Surfactants in the environment can change the interface characteristics of pollutants, and then drive the change of environmental behavior of pollutants. In this paper, we studied the physicochemical properties of complexes of polystyrene (PS) and polyethylene (PE) contaminated with sodium dodecyl benzene sulfonate (SDBS); the complexes are referred to as SPS and SPE, respectively. Taking oxytetracycline (OTC) and norfloxacin (NOR) as representatives of broad-spectrum antibiotics, the effects of SDBS on the adsorption behavior of PS and PE were analyzed and possible mechanisms were proposed. The results showed that SDBS could effectively combine with PS and PE to enhance the surface electronegativity and reduce the Brunner-Emmett-Teller (BET) specific surface area and porosity. The crystal structure remained basically unchanged, and the surface functional groups changed slightly. SDBS greatly enhanced the saturated adsorption capacities of PS and PE for OTC and NOR, and made adsorption easier, which reduced the Gibbs free energy of the adsorption system. The adsorption behaviors of SPS and SPE for the two antibiotics were consistent with the Elovich kinetic model and Sips isothermal model. SDBS enhanced the hydrophilicity of the microplastics, which facilitated their adsorption of antibiotics dissolved in water. SDBS could directly combine with antibiotics to form a complex, further increasing the adsorption capacity of the microplastics for antibiotics. The -SO3H in SDBS could combine with oxygen-containing functional groups and -NH2 in OTC and NOR. Non-ionic covalent bonds, electrostatic interactions, and hydrophobic attraction between the alkyl chain and benzene ring also played a role in adsorption. SDBS made it possible for MPs to load more types and quantities of pollutants and change their preferential adsorption selectivity, which significantly aggravated the environmental hazards.

An efficient factor for fast screening of high-performance two-dimensional metal-organic frameworks towards catalyzing the oxygen evolution reaction.

Two-dimensional (2D) metal-organic frameworks (MOFs) are promising materials for catalyzing the oxygen evolution reaction (OER) due to their abundant exposed active sites and high specific surface area. However, how to rapidly screen out highly-active 2D MOFs from numerous candidates is still a great challenge. Herein, based on the high-throughput density functional theory (DFT) calculations for 20 kinds of different transition metal-based MOFs, we propose a factor for fast screening of 2D MOFs for the OER under alkaline conditions (pH = 14.0), that is, when the Gibbs free energy change of the O-O bond formation (defined as ΔG 1) is located at ∼1.15 eV, the peak OER performance would be achieved. Based on the high-throughput calculation results, the prediction factor can be further simplified by replacing the Gibbs free energy with the sum of the associated single point energy (SPE) and a binding energy-dependent term. Guided by this factor, we successfully predicted and then obtained the high-performance Ni-based 2D MOFs. This factor would be a practical approach for fast screening of 2D MOF candidates for the OER, and also provide a meaningful reference for the study of other materials.

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.

Nanotechnology-based combinatorial phototherapy for enhanced cancer treatment.

Nanotechnology-based phototherapy has attracted enormous attention to cancer treatment owning to its non-invasiveness, high controllability and accuracy. Given the fast development of anti-tumor strategies, we summarize various examples of multifunctional nanosystems to highlight the recent advances in nanotechnology-based combinatorial phototherapy towards improving cancer treatment. The limitations of the monotherapeutic approach and the superiority of the photo-involved combinatorial strategies are discussed in each part. The future breakthroughs and clinical perspectives of combinatorial phototherapy are also outlooked. Our perspectives may inspire researchers to develop more effective phototherapy-based cancer-treating approaches.

Blood-brain barrier penetrating liposomes with synergistic chemotherapy for glioblastoma treatment.

Glioblastoma multiforme (GBM) is an aggressive and malignant brain tumor with high mortality. The current treatment strategies are still unsatisfactory for this devastating disease. Here, we developed a glucose-functionalized liposome (gLTP) that co-loads temozolomide (TMZ) and pro-apoptotic peptide (PAP) to achieve synergistic efficacy towards GBM. The gLTP can readily penetrate the blood-brain barrier via the glucose-GLUT1 pathway and release the TMZ and PAP in the cells. The PAP destroys the mitochondria and subsequently depletes ATP generation, making the GBM cells more sensitive to TMZ-mediated chemotherapy. gLTP exhibits the best anti-tumor effect on the subcutaneous brain tumor model compared to other treatments, including a single drug (TMZ or PAP) liposome and TMZ and PAP physical mixture. On the highly aggressive intracranial tumor model, gLTP can readily penetrate the BBB and efficiently deliver the drugs into the brain tumor, leading to striking improvements in total survival compared to the other treatments. This strategy potentially inspires new attempts to design more effective anti-GBM formulations.

Stimuli-responsive crosslinked nanomedicine for cancer treatment.

Nanomedicines are attractive paradigms to deliver drugs, contrast agents, immunomodulators, and gene editors for cancer therapy and diagnosis. However, the currently developed nanomedicine suffers from poor serum stability, premature drug release, and lack of responsiveness. Crosslinking strategy can be utilized to overcome these shortcomings by employing stimuli-responsive chemical bonds to tightly hold the nanostructure and releasing the payloads spatiotemporally in a highly controlled manner. In this Review, we summarize the recently ingenious design of the stimuli-responsive crosslinked nanomedicines (SCN) in the field of cancer treatment and their advances in circumventing the drawbacks of the conventional drug delivery system. We classify the SCNs into three categories based on the crosslinking strategies, including built-in, on-surface, and inter-particle crosslinking nanomedicines. Thanks to the stimuli-responsive crosslinkages, SCNs are capable of keeping robust stability during systemic circulation. They also respond to the particular tumoral conditions to experience a series of dynamic changes, such as the changes in size, surface charge, targeting moieties, integrity, and imaging signals. These characteristics allow them to efficiently overcome different biological barriers and substantially improve the drug delivery efficiency, tumor-targeting ability, and imaging sensitivities. With the examples discussed, we envision that our perspectives can inspire more attempts to engineer intelligent nanomedicine to achieve effective cancer therapy and diagnosis.