A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

The application of nanoparticles based on ferroptosis in cancer therapy.

Ferroptosis is a new form of non-apoptotic programmed cell death. Due to its effectiveness in cancer treatment, there are increasing studies on the application of nanoparticles based on ferroptosis in cancer therapy. In this paper, we present a summary of the latest progress in nanoparticles based on ferroptosis for effective tumor therapy. We also describe the combined treatment of ferroptosis with other therapies, including chemotherapy, radiotherapy, phototherapy, immunotherapy, and gene therapy. This summary of drug delivery systems based on ferroptosis aims to provide a basis and inspire opinions for researchers concentrating on exploring this field. Finally, we present some prospects and challenges for the application of nanotherapies to clinical treatment by promoting ferroptosis in cancer cells.

Autophagy-induced intracellular signaling fractional nano-drug system for synergistic anti-tumor therapy.

Autophagy inducers increase the sensitivity of tumor cells to chemotherapeutic drugs and enhance anti-tumor efficacy. An autophagy-induced intracellular signaling fractional nano-drug system was constructed for the co-delivery of the autophagy inducer rapamycin (RAPA) and the anti-tumor drug 9-nitro-20(S)-camptothecin (9-NC). Link peptides, including cathepsin B-sensitive peptides (Ala-Leu-Ala-Leu, ALAL), nucleus-targeting peptides (TAT, sequence: YGRKKRRQRRR), and chrysin (CHR)-modified hydrophobic biodegradable polymers (poly(-caprolactone)) (PCL), were grafted onto hyaluronic acid (HA) to yield two amphiphiles, HA-ALAL-PCL-CHR (CPAH) and HA-ALAL-TAT-PCL-CHR (CPTAH). Spherical RAPA- and 9-NC-loaded micelles were obtained by the self-assembly of amphiphiles comprising CPAH and RAPA and CPTAH and 9-NC. In this fractional nano-drug system, RAPA was released earlier than 9-NC, as CPAH as a RAPA carrier lacked a nucleus-targeting TAT (unlike CPTAH as an 9-NC carrier). RAPA induced autophagy in tumor cells and improved their sensitivity, whereas the secondary nucleus-targeting micelles directly delivered 9-NC to the nucleus, considerably improving anti-tumor efficacy. Immunofluorescence staining, acridine orange (AO) staining, and western blotting results demonstrated that the system induced a high level of autophagy in combination chemotherapy. The proposed system possesses a high level of cytotoxicity in vitro and in vivo and provides a potential method for enhancing anti-tumor efficacy in clinical settings.

Recent advances in anti-multidrug resistance for nano-drug delivery system.

Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field.

1T/2H Mixed Phase MoS2 Nanosheets Integrated by a 3D Nitrogen-Doped Graphene Derivative for Enhanced Electrocatalytic Hydrogen Evolution.

Molybdenum disulfide (MoS2) has become one of the most promising non-platinum-based electrocatalysts for the hydrogen evolution reaction (HER) because of its unique layered structure. However, the catalytic performance of the thermodynamically stable MoS2 is hindered by its poor conductivity and scarce active sites. We developed a 3D porous N-doped graphene derivative-integrated metal-semiconductor (1T-2H) mixed phase MoS2 (MNG) using urea as a doping reagent. The highly exposed active sites were achieved by inducing the phase transition of MoS2 from 2H phase to 1T phase and the inclusion of highly N-incorporated reduced graphene oxide, both of which were simultaneously realized by optimizing the concentration of the doping reagent. Moreover, the charge/proton transfer was enhanced by the well-designed porous architecture and hydrophilic 1T-MoS2. With these advantages, the optimized MNG-40 catalyst has a small overpotential of 157 mV at a cathodic current density of 10 mA cm-2, a relatively low Tafel slope of 45.8 mV dec-1, and an excellent stability. This work represents a new strategy to design higher-performance HER catalysts and provides new insights into the structural regulation of metal composite transitions.