Inverted perovskite solar cells using dimethylacridine-based dopants.

Doping of perovskite semiconductors1 and passivation of their grain boundaries2 remain challenging but essential for advancing high-efficiency perovskite solar cells. Particularly, it is crucial to build perovskite/indium tin oxide (ITO) Schottky contact based inverted devices without predepositing a layer of hole-transport material3-5. Here we report a dimethylacridine-based molecular doping process used to construct a well-matched p-perovskite/ITO contact, along with all-round passivation of grain boundaries, achieving a certified power conversion efficiency (PCE) of 25.39%. The molecules are shown to be extruded from the precursor solution to the grain boundaries and the bottom of the film surface in the chlorobenzene-quenched crystallization process, which we call a molecule-extrusion process. The core coordination complex between the deprotonated phosphonic acid group of the molecule and lead polyiodide of perovskite is responsible for both mechanical absorption and electronic charge transfer, and leads to p-type doping of the perovskite film. We created an efficient device with a PCE of 25.86% (reverse scan) and that maintained 96.6% of initial PCE after 1,000 h of light soaking.

ROS-Inducing Micelles Sensitize Tumor-Associated Macrophages to TLR3 Stimulation for Potent Immunotherapy.

One approach to cancer immunotherapy is the repolarization of immunosuppressive tumor-associated macrophages (TAMs) to antitumor M1 macrophages. The present study developed galactose-functionalized zinc protoporphyrin IX (ZnPP) grafted poly(l-lysine)- b-poly(ethylene glycol) polypeptide micelles (ZnPP PM) for TAM-targeted immunopotentiator delivery, which aimed at in vivo repolarization of TAMs to antitumor M1 macrophages. The outcomes revealed that ROS-inducing ZnPP PM demonstrated specificity for the in vitro and in vivo targeting of macrophages, elevated the level of ROS, and lowered STAT3 expression in BM-TAMs. Poly I:C (PIC, a TLR3 agonist)-loaded ZnPP PM (ZnPP PM/PIC) efficiently repolarized TAMs to M1 macrophages, which were reliant on ROS generation. Further, ZnPP PM/PIC substantially elevated the activated NK cells and T lymphocytes in B16-F10 melanoma tumors, which caused vigorous tumor regression. Therefore, the TAM-targeted transport of an immunologic adjuvant with ZnPP-grafted nanovectors may be a potential strategy to repolarize TAMs to M1 macrophages in situ for effective cancer immunotherapy.

A Single-Step Hydrothermal Route to 3D Hierarchical Cu2 O/CuO/rGO Nanosheets as High-Performance Anode of Lithium-Ion Batteries.

As anodes of Li-ion batteries, copper oxides (CuO) have a high theoretical specific capacity (674 mA h g-1 ) but own poor cyclic stability owing to the large volume expansion and low conductivity in charges/discharges. Incorporating reduced graphene oxide (rGO) into CuO anodes with conventional methods fails to build robust interaction between rGO and CuO to efficiently improve the overall anode performance. Here, Cu2 O/CuO/reduced graphene oxides (Cu2 O/CuO/rGO) with a 3D hierarchical nanostructure are synthesized with a facile, single-step hydrothermal method. The Cu2 O/CuO/rGO anode exhibits remarkable cyclic and high-rate performances, and particularly the anode with 25 wt% rGO owns the best performance among all samples, delivering a record capacity of 550 mA h g-1 at 0.5 C after 100 cycles. The pronounced performances are attributed to the highly efficient charge transfer in CuO nanosheets encapsulated in rGO network and the mitigated volume expansion of the anode owing to its robust 3D hierarchical nanostructure.

Tumor associated macrophage-targeted microRNA delivery with dual-responsive polypeptide nanovectors for anti-cancer therapy.

Repolarizing Tumor-associated macrophages (TAMs) to anti-tumor M1 macrophages with microRNA (miR) is a plausible approach for cancer treatment. However, how to achieve TAM-targeted miR delivery remains a challenge. The present study generated redox/pH dual-responsive hybrid polypeptide nanovectors, which consisted of self-crosslinked redox-responsive nanoparticles based on galactose-functionalized n-butylamine-poly(l-lysine)-b-poly(l-cysteine) polypeptides (GLC) coated with DCA-grafted sheddable PEG-PLL (sPEG) copolymers. The ex vivo study showed that sPEG shielded cationic GLC core at physiological pH but quickly shed off to re-expose GLC due to it charge reversible property. Encapsulation with sPEG/GLC nanovectors effectively facilitated macrophage-targeted miR delivery at the acidic condition but diminished miR uptake at neutral pH. Administration of miR155-loaded sPEG/GLC (sPEG/GLC/155) nanocomplexes increased miR155 expression in TAMs about 100-400 folds both in vitro and in vivo. sPEG/GLC/155 also effectively repolarized immunosuppressive TAMs to anti-tumor M1 macrophages through elevating M1 macrophage markers (IL-12, iNOS, MHC II) and suppressing M2 macrophage markers (Msr2 and Arg1) in TAMs. Moreover, the treatment of sPEG/GLC/155 significantly increased activated T lymphocytes and NK cells in tumors, which consequently led to robust tumor regression. Hence, TAM-targeted delivery of miR with redox/pH dual-responsive sPEG/GLC nanovectors could be a promising approach to re-polarize TAMs to M1 macrophages in situ and induce tumor regression.

Redox-responsive dextran based theranostic nanoparticles for near-infrared/magnetic resonance imaging and magnetically targeted photodynamic therapy.

Photodynamic therapy (PDT) is a site-specific treatment of cancer using much lower optical power densities with minimal nonspecific damage to normal tissues. To improve the therapeutic efficiency of PDT, we fabricated a multifunctional theranostic nanoparticle system (DSSCe6@Fe3O4 NPs) by loading Fe3O4 nanoparticles in redox-responsive chlorin e6 (Ce6)-conjugated dextran nanoparticles for near-infrared (NIR)/magnetic resonance (MR) dual-modality imaging and magnetic targeting. The obtained DSSCe6@Fe3O4 NPs demonstrated a uniform nanospherical morphology consisting of Fe3O4 clusters. The fluorescence signal of Ce6 of this theranostic system could turn "ON" from a self-quenching state in a reductive intracellular environment. T2-Weighted MR imaging revealed a high transverse relaxivity (r2) measured to be 194.4 S-1 mM-1, confirming that it was also a distinctive contrast agent in T2-weighted MR imaging. Confocal images and flow cytometry results showed that the cellular uptake of DSSCe6@Fe3O4 NPs was enhanced effectively under an extra magnetic field, which resulted in promoted PDT therapeutic efficiency. In vivo MR imaging showed that DSSCe6@Fe3O4 NPs effectively accumulated in tumors under an extra magnetic field. These results illustrated that the DSSCe6@Fe3O4 NPs could be a promising theranostic system for both NIR/MR imaging-guided PDT precision therapy.

Silencing c-Rel in macrophages dampens Th1 and Th17 immune responses and alleviates experimental autoimmune encephalomyelitis in mice.

Autoimmune Th1 and Th17 responses are critical for the development of central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Although macrophages play important roles in the development of Th1 and Th17 responses, whether modulating macrophage gene transcription can diminish the Th1- and Th17 cell-induced CNS pathology is unclear. In this study, we successfully silenced the expression of the transcription factor c-Rel in macrophages of mice with EAE (including those infiltrating the CNS) using chemically modified c-Rel-specific siRNAs delivered by nanoparticles. Knocking down c-Rel in macrophages in vitro inhibited expression of NF-κB targets, such as pro-inflammatory cytokines interleukin 1ß (IL-1ß) and p40 of interleukin 12 (IL-12)/interleukin 23 (IL-23), in macrophages, leading to reduced interferon γ (IFN-γ) and interleukin 17A (IL-17A) production by co-cultured MOG-specific T cells from EAE mice. Such effects correlated with diminished T-cell infiltration in the CNS, reduced clinical symptoms, as well as downregulated pathogenic Th1 and Th17 responses in EAE mice. Taken together, our findings indicate that targeting c-Rel in macrophages dampens CNS-specific Th1 and Th17 immune responses, and can be effective for treating autoimmune diseases of the CNS.

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis.

Immunosuppressive tumor-associated dendritic cells (TADCs) are potential targets for cancer therapy. However, their poor responsiveness to TLR stimulation is a major obstacle for achieving successful cancer immunotherapy. In the current study, we reported a dysregulated miR-148a/DNA methyltransferase (DNMT)1/suppressor of cytokine signaling (SOCS)1 axis as a unique mechanism for dampened TLR stimulation in TADCs. The results showed that aberrantly elevated miR-148a in bone marrow-derived TADC (BM-TADC) abolished polyinosinic-polycytidylic acid (poly I:C) or LPS-induced dendritic cell maturation through directly suppressing DNMT1 gene, which consequently led to the hypomethylation and upregulation of SOCS1, the suppressor of TLR signaling. In contrast, miR-148a inhibitor (miR-148ai) effectively rescued the expression of DNMT1 and decreased SOCS1 in BM-TADCs, thereby recovering their sensitivity to TLR3 or TLR4 stimulation. To further reprogram TADCs in vivo, miR-148ai was coencapsulated with poly I:C and OVA by cationic polypeptide micelles to generate integrated polypeptide micelle/poly I:C (PMP)/OVA/148ai nanovaccine, which was designed to simultaneously inhibit miR-148a and activate TLR3 signaling in TADCs. The immunization of PMP/OVA/148ai nanovaccine not only effectively modulated the miR-148a/DNMT1/SOCS1 axis in the spleen, but also significantly increased mature dendritic cells both in the spleen and in tumor microenvironment. Moreover, PMP/OVA/148ai ameliorated tumor immunosuppression through reducing regulatory T cells and myeloid-derived suppressor cells, thereby leading to potent anticancer immune responses and robust tumor regression with prolonged survival. This study proposes a nanovaccine-based immunogene therapy with the integration of miR-148a inhibition and TLR3 stimulation as a novel therapeutic approach to boost anticancer immunity by reprogramming TADCs in vivo.

Synergistic Therapy of Doxorubicin and miR-129-5p with Self-Cross-Linked Bioreducible Polypeptide Nanoparticles Reverses Multidrug Resistance in Cancer Cells.

Although microRNAs (miRs) are short endogenous noncoding RNAs playing a central role in cancer initiation and progression, their therapeutic potential in overcoming multidrug resistance (MDR) remains unclear. In the present study, we developed self-cross-linked biodegradable poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-cysteine) (LCss) polypeptide nanoparticles to codeliver DOX and miR-129-5p, which aimed to overcome MDR in cancer cells. The results showed that LCss nanoparticles effectively coencapsulated DOX and miR with great stability, but quickly disassembled and released their payload in a bioreducible environment. The codelivery of miR-129-5p and DOX with LCss (DLCss/miR) significantly increased miR-129-5p expression over 100-fold in MCF-7/ADR cells, which effectively overcame MDR by directly inhibiting P-glycoprotein (P-gp), thereby increasing intracellular DOX accumulation and cytotoxicity in MCF-7/ADR cells. Furthermore, miR-129-5p also partially diminished cyclin-dependent kinase 6 (CDK6), and synergized with DOX to simultaneously decrease S phase and induce G2 phase cell cycle arrest, thereby further enhancing the chemosensitivity of MCF-7/ADR cells. Hence, redox-responsive LCss nanoparticles are potent nanocarrier for combinational drug-miR therapy, which could be a promising strategy to overcome MDR in cancer cells.

In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery.

Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR(+)) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR(+) HeLa and FR(-) A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.

Treating psoriasis by targeting its susceptibility gene Rel.

Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis.

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo.

Although cancer vaccine-based immunotherapy holds great potential for cancer treatment, tumor-induced dendritic cell (DC) dysfunction remains to be the major obstacle for developing effective vaccines. Compared with normal DCs, tumor-associated DCs (TADCs) are less matured with poor responsiveness to Toll-like receptor (TLR) stimulation, which has been related with STAT3 hyperactivity. In the present study, Poly I:C (PIC, a TLR3 agonist), STAT3 siRNA and OVA antigen were co-encapsulated by poly (ethylene glycol)-b-poly (L-lysine)-b-poly (L-leucine) (PEG-PLL-PLLeu) polypeptide micelles to generate PMP/OVA/siRNA nanovaccine, which was aimed to effectively overcome DC dysfunction in vivo by deleting STAT3 gene in situ. The results showed that PMP/OVA/siRNA simultaneously facilitated the cellular uptake of OVA antigen and siRNA about 3-200 folds, and decreased STAT3 expression in TADCs over 50% both in vitro and in vivo. PMP/OVA/siRNA also elevated CD86 and CD40 expression as well as IL-12 production by TADCs more effectively than PMP/OVA did, indicating its strong potency of inducing TADC maturation and activation. Moreover, the immunization of PMP/OVA/siRNA rather than PMP/OVA effectively abrogated immunosuppression in the tumor microenvironment by increasing mature DCs and decreasing immunosuppressive cells in tumor-draining lymph nodes, which thereby led to potent anti-tumor immune responses and dramatic tumor regression with prolonged survival. Hence, in vivo co-delivery of immunopotentiator (PIC) and immunosuppressive gene silencer (STAT3 siRNA) by nanovaccines are expected to be a promising strategy to improve the therapeutic efficacy of cancer vaccines by modulating TADCs and overcoming tumor immunosupression.

ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy.

Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA-DOX-NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA-NP or siRNA-DOX-NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment.

Polypeptide micelles with dual pH activatable dyes for sensing cells and cancer imaging.

pH is an important control parameter for maintenance of cell viability and tissue functions. pH monitoring provides valuable information on cell metabolic processes and the living environment. In this study, we prepared dual pH-sensitive, fluorescent dye-loaded polypeptide nanoparticles (DPNs) for ratiometric sensing of pH changes in living cells. DPNs contain two types of dyes: N-(rhodamine B) lactam cystamine (RBLC), an acid activatable fluorescent dye with increased fluorescence in an acidic environment, and fluorescein isothiocyanate (FITC), a base activatable fluorescent dye with enhanced fluorescence in an alkaline environment. Hence, DPNs exhibited a dual response signal with strong red fluorescence and weak green fluorescence under acidic conditions; in contrast, they showed strong green fluorescence and almost no red fluorescence under alkaline and neutral conditions. The favorable inverse pH responses of the two fluorescent dyes resulted in ratiometric pH determination for DPNs with an optimized pH-sensitive range of pH 4.5-7.5. Quantitative analysis of the intracellular pH of intact MCF-7 cells has been successfully demonstrated with our nanosensor. Moreover, single acid activatable fluorescent dye doped polypeptide nanoparticles that only contained RBLC can distinguish tumor tissue from normal tissue by monitoring the acidic extracellular environment.

Polypeptide cationic micelles mediated co-delivery of docetaxel and siRNA for synergistic tumor therapy.

Combination of two or more therapeutic strategies with different mechanisms can cooperatively impede tumor growth. Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanoparticle (NP) provides a rational strategy for combined cancer therapy. Here, we prepared polypeptide micelle nanoparticles (NPs) of a triblock copolymer poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) to systemically codeliver docetaxel (DTX) and siRNA-Bcl-2 for an effective drug/gene vector. The hydrophobic PLLeu core entrapped with anticancer drugs, while the PLL polypeptide cationic backbone allowed for electrostatic interaction with the negatively charged siRNA. The resulting micelle NP exhibited very stable, good biocompatible and excellent passive targeted properties. The micelle complexes with siRNA-Bcl-2 effectively knocked down the expression of Bcl-2 mRNA and protein. Moreover, the co-delivery system of DTX and siRNA-Bcl-2 (DTX-siRNA-NPs) obviously down-regulation of the anti-apoptotic Bcl-2 gene and enhanced antitumor activity with a smaller dose of DTX, resulting the significantly inhibited tumor growth of MCF-7 xenograft murine model as compared to the individual siRNA and only DTX treatments. Our results demonstrated well-defined PEG-PLL-PLLeu polypeptide cationic micelles with the excellent synergistic effect of DTX and siRNA-Bcl-2 in combined cancer therapy.

Self-assembled cationic micelles based on PEG-PLL-PLLeu hybrid polypeptides as highly effective gene vectors.

Developing safe and effective nonviral gene vector is highly crucial for successful gene therapy. In the present study, we designed a series of biodegradable micelles based on hybrid polypeptide copolymers of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) for efficient gene delivery. A group of amphiphilic PEG-PLL-PLLeu hybrid polypeptide copolymers were synthesized by ring-opening polymerization of N-carboxyanhydride, and the chemical structure of each copolymer was characterized by (1)H NMR and FT-IR spectroscopy measurement. The PEG-PLL-PLLeu micelles were positively charged with tunable sizes ranging from 40 to 90 nm depending on the length of PLL and PLLeu segment. Compared with PEG-PLL copolymers, PEG-PLL-PLLeu micelles demonstrated significantly higher transfection efficiency and less cytotoxicity. Furthermore, the transfection efficiency and biocompatibility of the micelles can be simultaneously improved by tuning the length of PLL and PLLeu segments. The transfection efficiency of PEG-PLL-PLLeu micelles in vivo was two to three times higher than that of PEI(25k), which was attributable to their capability of promoting DNA condensation and cell internalization as well as successful lysosome escape. Hence well-defined PEG-PLL-PLLeu micelles would serve as highly effective nonviral vectors for in vivo gene delivery.

Tetrabutyl titanate-controlled polymerization of epsilon-caprolactone at ambient temperature.

A low cost and environmentally benign process for tetrabutyl titanate-controlled ring-opening polymerization of epsilon-caprolactone at ambient temperature of 10-40 degrees C is introduced affording poly(epsilon-caprolactone) with pre-designed molecular weights and narrow molecular weight distribution.