Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy.

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.

A Metal-Phenolic Nanosensitizer Performs Hydrogen Sulfide-Reprogrammed Oxygen Metabolism for Cancer Radiotherapy Intensification and Immunogenicity.

Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H2 S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H2 S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics.

Hydrogen Polysulfide Biosignal-Responsive Polymersomes as a Nanoplatform for Distinguishing Intracellular Reactive Sulfur Species (RSS).

Reactive sulfur species (RSS) are a family of crucial biosignals for regulating cell processes. Among these, hydrogen polysulfide (H2 Sn , n ≥ 2) is a hallmark of tumor suppressor activation and regarded as the actual regulator to mediate sulfur-related biology. However, high effective recognition of intracellular H2 Sn is insurmountable due to its extremely low concentration and the disturbance of RSS analogues. Here an H2 Sn -responsive macromolecule that can distinguish H2 Sn from intracellular RSS through polymer degradation in ultrasensitive and highly selective manner is reported. This kind of polymers can further self-assemble into vesicular nanostructure. Upon cell uptake, they can be function as "all-in-one" H2 Sn -nanoplatforms, in order to fulfill multiple ambitious tasks including monitoring the H2 Sn biosynthetic pathways, unraveling the puzzles of H2 Sn -mediated cellular events, and conducting H2 Sn pathological milieu-specific drug delivery.

Octahedral Pd@Pt1.8Ni core-shell nanocrystals with ultrathin PtNi alloy shells as active catalysts for oxygen reduction reaction.

Forming core-shell and alloy structures offers generally two ways to design efficient Pt-based catalysts for oxygen reduction reaction (ORR). Here, we combined these two strategies and invented a versatile aqueous route to synthesize octahedral Pd@Pt1.8Ni core-shell nanocrystals. The Pt/Ni atomic ratios in the resultant shells can be varied from 0.6 to 1.8, simply by changing the amounts of Pt and Ni precursors, with the other conditions unchanged. Experimental studies showed that the mass activities of as-prepared catalysts were 5 times higher than that of the commercial Pt/C. We believe that the ultrathin PtNi shells enclosed by {111} facets made it possible to reduce the Pt content while retaining the catalytic activity toward ORR. This strategy may be extended to the preparation of other multimetallic nanocrystals with shaped and ultrathin alloy shells, which is conducive to design highly active catalysts.

Synthesis of bottlebrush polystyrenes with uniform, alternating, and gradient distributions of brushes via living anionic polymerization and hydrosilylation.

By combining living anionic polymerization and hydrosilylation, densely grafted bottlebrush polymers with controlled spacing of branch points are prepared. Dimethyl(4-vinylphenyl)silane and dimethyl(4-(1-phenylvinyl)phenyl)silane are anionically (co)polymerized to synthesize uniform, alternating, and gradient in-chain silyl-hydride (Si-H) functionalized backbones. The spacing of branch points is controlled effectively by regulating the distribution of Si-H groups along the backbones. Three backbones with a similar number of Si-H groups but variable distributions are used to synthesize corresponding bottlebrush polymers via hydrosilylation between the backbones and chain-end vinyl functionalized polystyrene. The uniformly grafted bottlebrush exhibits the highest hydrodynamic radius (Rh ) of 5.6 nm and the lowest Tg of 79 °C which may be attributed to its compact grafted structure. This methodology exhibits high efficiency and convenience for the construction of bottlebrushes with controlled distribution of brushes.

A metal-polyphenolic nanosystem with NIR-II fluorescence-guided combined photothermal therapy and radiotherapy.

Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.

Polyphenol-based nanoplatform for MRI/PET dual-modality imaging guided effective combination chemotherapy.

Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe3+ or Mn2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe3+ or Mn2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.

Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine.

INTRODUCTION: Berberine (BBR) is a plant-derived benzylisoquinoline alkaloid and has been demonstrated to be a potential treatment for various chronic diseases. The poor water solubility and P-glycoprotein (Pgp)-mediated drug efflux are the main challenges for its further application in a clinical setting. MATERIALS AND METHODS: In this study, a Brij-S20 (BS20)-modified nanocrystal formulation (BBR-BS20-NCs) has been developed and investigated with the purpose of improving the intestinal absorption of BBR. The physicochemical properties of the developed BBR-BS20-NCs were characterized and the enhancement of the BBR-BS20-NCs on BBR absorption were investigated both in vitro and in vivo. RESULTS: The results indicated that BS20 could significantly enhance the intracellular uptake of BBR in MDCK-MDR1 cells via a short-term and reversible modulation on the Pgp function, accompanied by a marked increase in Pgp mRNA expression but without significant influence on the Pgp protein expression. Moreover, the morphology of the prepared BBR-BS20-NCs was observed to be prism-like, with a smooth surface and an average diameter of 148.0 ± 3.2 nm. Compared to raw BBR and physical mixture, BBR-BS20-NCs facilitated the dissolution rate and extent of release of BBR in aqueous solution, and further increased the absorption of BBR in MDCK-MDR1 monolayer by overcoming the Pgp-mediated secretory transport (Papp[BL-AP] values of 2.85 ± 0.04 × 10-6 cm/s, 2.21 ± 0.14 × 10-6 cm/s, and 2.00 ± 0.07 × 10-6 cm/s for pure BBR, physical mixture, and BBR-BS20-NCs, respectively). Significant improvements in the maximum concentration observed (Cmax) and area under drug concentration-time curve (AUC0-t) of BBR-BS20-NCs were obtained in pharmacokinetic studies compared to pure BBR, and the relative bioavailability of BBR-BS20-NCs to pure BBR was 404.1%. CONCLUSION: The developed BBR-BS20-NCs combine the advantages of nanocrystal formulation and functional excipient. The novel pharmaceutical design provides a new strategy to improve the oral bioavailability of those drugs with both poor water solubility and Pgp-mediated efflux.