CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy.

Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases.

Metal-Organic Frameworks as Intelligent Drug Nanocarriers for Cancer Therapy.

Metal-organic frameworks (MOFs) are crystalline porous materials with periodic network structures formed by self-assembly of metal ions and organic ligands. Attributed to their tunable composition and pore size, ultrahigh surface area (1000-7000 m2/g) and pore volume (1.04-4.40 cm3/g), easy surface modification, appropriate physiological stability, etc., MOFs have been widely used in biomedical applications in the last two decades, especially for the delivery of bioactive agents. In the initial stage, MOFs were widely used to load small molecule drugs with ultra-high doses. Whereafter, more recent work has focused on the load of biomacromolecules, such as nucleic acids and proteins. Over the past years, we have devoted extensive effort to investigate the function of MOF materials for bioactive agent delivery. MOFs can be used not only as an intelligent nanocarrier to deliver or protect bioactive agents but also as an activator for their release or activation in response to the different microenvironments. Altogether, this review details the current progress of MOF materials for bioactive agent delivery and looks into their future development.

An Ion-Enhanced Oncolytic Virus-Like Nanoparticle for Tumor Immunotherapy.

T lymphocytes (T cells) are essential for tumor immunotherapy. However, the insufficient number of activated T cells greatly limits the efficacy of tumor immunotherapy. Herein, we proposed an oncolytic virus-mimicking strategy to enhance T cell recruitment and activation for tumor treatment. We constructed an oncolytic virus-like nanoplatform (PolyIC@ZIF-8) that was degraded in the acidic tumor environment to release PolyIC and Zn2+ . The released PolyIC exhibited an oncolytic virus-like function that induced tumor cell apoptosis and promoted T cell recruitment and activation through a tumor antigen-dependent manner. More importantly, the released Zn2+ not only enhanced T cell recruitment by inducing CXCL9/10/11 expression but also promoted T cell activation to increase interferon-γ (INF-γ) expression by inducing the phosphorylation of ZAP-70 via a tumor antigen-independent manner. This Zn2+ -enhanced oncolytic virus-mimicking strategy provides a new approach for tumor immunotherapy.

NIR-Triggered Intracellular H+ Transients for Lamellipodia-Collapsed Antimetastasis and Enhanced Chemodynamic Therapy.

In solid tumors, tumor invasion and metastasis account for 90 % of cancer-related deaths. Cell migration is steered by the lamellipodia formed at the leading edge. These lamellipodia can drive the cell body forward by its mechanical deformation regulated by cofilin. Inhibiting cofilin activity can cause significant defects in directional lamellipodia formation and the locomotory capacity of cell invasion, thus contributing to antimetastatic treatment. Herein, a near infrared light (NIR)-controlled nanoscale proton supplier was designed with upconversion nanoparticles (UCNPs) as a core coated in MIL-88B for interior photoacids loading; this photoacids loading can boost H+ transients in cells, which converts the cofilin to an inactive form. Strikingly, inactive cofilin loses the ability to mediate lamellipodia deformation for cell migration. Additionally, the iron, which serves as a catalyticaly active center in MIL-88B, initiates an enhanced Fenton reaction due to the increased H+ in the tumor, ultimately achieving intensive chemodynamic therapy (CDT). This work provides new insight into H+ transients in cells, which not only regulates cofilin protonation for antimetastatic treatment but also improves chemodynamic therapy.

Regulating the Coordination Environment of MOF-Templated Single-Atom Nickel Electrocatalysts for Boosting CO2 Reduction.

The general synthesis and control of the coordination environment of single-atom catalysts (SACs) remains a great challenge. Herein, a general host-guest cooperative protection strategy has been developed to construct SACs by introducing polypyrrole (PPy) into a bimetallic metal-organic framework. As an example, the introduction of Mg2+ in MgNi-MOF-74 extends the distance between adjacent Ni atoms; the PPy guests serve as N source to stabilize the isolated Ni atoms during pyrolysis. As a result, a series of single-atom Ni catalysts (named NiSA -Nx -C) with different N coordination numbers have been fabricated by controlling the pyrolysis temperature. Significantly, the NiSA -N2 -C catalyst, with the lowest N coordination number, achieves high CO Faradaic efficiency (98 %) and turnover frequency (1622 h-1 ), far superior to those of NiSA -N3 -C and NiSA -N4 -C, in electrocatalytic CO2 reduction. Theoretical calculations reveal that the low N coordination number of single-atom Ni sites in NiSA -N2 -C is favorable to the formation of COOH* intermediate and thus accounts for its superior activity.

Yolk-Shell Structured Au Nanostar@Metal-Organic Framework for Synergistic Chemo-photothermal Therapy in the Second Near-Infrared Window.

Light-sensitive yolk-shell nanoparticles (YSNs) as remote-controlled and stimuli-responsive theranostic platforms provide an attractive method for synergistic cancer therapy. Herein, a kind of novel stimuli-responsive multifunctional YSNs has been successfully constructed by integrating star-shaped gold (Au star) nanoparticles as the second near-infrared (NIR-II) photothermal yolks and biodegradable crystalline zeolitic imidazolate framework-8 (ZIF-8) as the shells. In this platform, a chemotherapeutic drug (doxorubicin hydrochloride, DOX) was encapsulated into the cavity, which can show the behavior of controlled release due to the degradation process of ZIF-8 in the mildly acidic tumor microenvironment. Upon the 1064 nm (NIR-II biowindow) laser irradiation, gold nanostar@ZIF-8 (Au@MOF) nanoparticles exhibited outstanding synergistic anticancer effect based on their photothermal and promoted cargo release properties. Moreover, the strong NIR region absorbance endows the Au@MOF of NIR thermal imaging and photoacoustic (PA) imaging properties. This work contributes to design a stimuli-responsive "all-in-one" nanocarrier that realizes bimodal imaging diagnosis and chemo-photothermal synergistic therapy.

O2-Cu/ZIF-8@Ce6/ZIF-8@F127 Composite as a Tumor Microenvironment-Responsive Nanoplatform with Enhanced Photo-/Chemodynamic Antitumor Efficacy.

Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic system, O2-Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O2-enhanced combination therapy. Notably, the doped Cu2+ doubles the O2 storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O2 reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu+ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H2O2. The accompanying O2 will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.

Monodispersed Copper(I)-Based Nano Metal-Organic Framework as a Biodegradable Drug Carrier with Enhanced Photodynamic Therapy Efficacy.

Photodynamic therapy (PDT) has emerged as an alternative treatment of cancers. However, the therapeutic efficiency of PDT is severely limited by the microenvironment of insufficient oxygen (O2) supply and overexpression of glutathione (GSH) in the tumor. Herein, a biodegradable O2-loaded CuTz-1@F127 (denoted as CuTz-1-O2@F127) metal-organic framework (MOF) therapeutic platform is presented for enhanced PDT by simultaneously overcoming intracellular hypoxia and reducing GSH levels in the tumor. The Cu(I)-based MOF is capable of a Fenton-like reaction to generate •OH and O2 in the presence of H2O2 under NIR irradiation. Meanwhile, the CuTz-1-O2@F127 nanoparticles (NPs) can release adsorbed O2, which further alleviates intracellular hypoxia. In addition, the CuI in CuTz-1@F127 can react with intracellular GSH to reduce the excess GSH. In this way, the efficiency of PDT is greatly enhanced. After tail intravenous injection, the NPs show high antitumor efficacy through a synergistic effect under 808 nm laser irradiation. More importantly, the NPs are biodegradable. In vivo biodistribution and excretion experiments demonstrate that a total of nearly 90% of the NPs can be excreted via feces and urine within 30 d, which indicates significant prospects in the clinical treatment of cancers.

MnFe2O4-decorated large-pore mesoporous silica-coated upconversion nanoparticles for near-infrared light-induced and O2 self-sufficient photodynamic therapy.

The limited light penetration depth and tumor hypoxia are two natural shortcomings of photodynamic therapy (PDT). Overcoming these two issues within a single system is still a great challenge. Herein, photosensitizer (PS)-loaded and PEG-modified MnFe2O4-decorated large-pore mesoporous silica-coated ß-NaYF4:20%Yb,2%Er@ß-NaYF4 upconversion nanoparticles (UCMnFe-PS-PEG) as excellent PDT agents are successfully prepared for NIR light-mediated and O2 self-sufficient PDT. The large mesoporous structure observably increases PS loading efficiency (11.33 wt%) and the green luminescence from upconversion nanoparticles activated by NIR is able to activate PSs to generate ROS effectively. In addition, sub-10 nm MnFe2O4 nanoparticles work as a Fenton catalyst to generate O2in situ. In vivo experiments further prove that UCMnFe-PS-PEG not only provides magnetic guidance to the tumor, but also overcomes tumor hypoxia and dramatically enhances PDT efficiency. Furthermore, in vivo MR and UCL imaging are performed for accurate cancer therapy. We believe that the successful construction of the multifunctional UCMnFe-PS-PEG provides more revelations for developing advanced nano-drug systems for cancer therapy.

Postsynthetic Ligand Exchange of Metal-Organic Framework for Photodynamic Therapy.

Attributed to the large pore size and excellent stability, the metal-organic framework (MOF), NU-1000, which is formed by the coordination of Zr cluster and 1,3,6,8-tetrakis( p-benzoic acid)pyrene (H4TBAPy) ligand, has been widely studied in the catalysis research field; however, only a few reports about the biomedical application of NU-1000 could be found in the open literature. In this study, a functional ligand, tetrakis(4-carboxyphenyl)porphyrin (TCPP), was introduced into NU-1000 via a postsynthetic ligand exchange method and the resulting mixed ligand MOF has an excellent photodynamic effect. Finally, in vitro and in vivo assessment about the antitumor efficacy was investigated for the first time. It demonstrates the feasibility of TCPP-substituted NU-1000 to be used for photodynamic therapy and also provides an alternative approach to enrich the function of MOF for various applications via a postsynthetic method.

Improving MOF stability: approaches and applications.

Metal-organic frameworks (MOFs) have been recognized as one of the most important classes of porous materials due to their unique attributes and chemical versatility. Unfortunately, some MOFs suffer from the drawback of relatively poor stability, which would limit their practical applications. In the recent past, great efforts have been invested in developing strategies to improve the stability of MOFs. In general, stable MOFs possess potential toward a broader range of applications. In this review, we summarize recent advances in the design and synthesis of stable MOFs and MOF-based materials via de novo synthesis and/or post-synthetic structural processing. Also, the relationships between the stability and functional applications of MOFs are highlighted, and finally, the subsisting challenges and the directions that future research in this field may take have been indicated.

Interfacially synthesized Fe-soc-MOF nanoparticles combined with ICG for photothermal/photodynamic therapy.

Recently, fabrication of nanoscale MOFs (NMOFs) has attracted great attention for biomedical applications. NMOFs not only maintain the structural diversity and physicochemical properties of bulk MOFs, but also possess suitable dimensions, making them potential nanocarriers for imaging agents and drug molecules. In this work, highly monodispersed Fe-soc-MOF nanoparticles (about 100 nm) were fabricated through the liquid-solid-solution (LSS) method. Indocyanine green (ICG) was conjugated to the surface-modified Fe-soc-MOF to construct a multifunctional theranostic platform. The Fe-soc-MOF@PEG-NH2-ICG nanoparticles (FPINs) were tested for photothermal therapy (PTT)/photodynamic therapy (PDT) both in vitro and in vivo. Due to their low toxicity, good biocompatibility and excellent photothermal/photodynamic effect, the as-synthesized FPINs could be used to inhibit and kill cancer cells efficiently under the 808 nm laser irradiation.

A Hollow-Structured CuS@Cu2 S@Au Nanohybrid: Synergistically Enhanced Photothermal Efficiency and Photoswitchable Targeting Effect for Cancer Theranostics.

It is of great importance in drug delivery to fabricate multifunctional nanocarriers with intelligent targeting properties, for cancer diagnosis and therapy. Herein, hollow-structured CuS@Cu2 S@Au nanoshell/satellite nanoparticles are designed and synthesized for enhanced photothermal therapy and photoswitchable targeting theranostics. The remarkably improved photothermal conversion efficiency of CuS@Cu2 S@Au under 808 nm near-infrared (NIR) laser irradiation can be explained by the reduced bandgap and more circuit paths for electron transitions for CuS and Cu2 S modified with Au nanoparticles, as calculated by the Vienna ab initio simulation package, based on density functional theory. By modification of thermal-isomerization RGD targeting molecules and thermally sensitive copolymer on the surface of nanoparticles, the transition of the shielded/unshielded mode of RGD (Arg-Gly-Asp) targeting molecules and shrinking of the thermally sensitive polymer by NIR photoactivation can realize a photoswitchable targeting effect. After loading an anticancer drug doxorubicin in the cavity of CuS@Cu2 S@Au, the antitumor therapy efficacy is greatly enhanced by combining chemo- and photothermal therapy. The reported nanohybrid can also act as a photoacoustic imaging agent and an NIR thermal imaging agent for real-time imaging, which provides a versatile platform for multifunctional theranostics and stimuli-responsive targeted cancer therapy.

Synthesis of highly monodispersed Ga-soc-MOF hollow cubes, colloidosomes and nanocomposites.

Ga-soc-MOF hollow cubes with an average size of about 300 nm were prepared by a polyvinylpyrrolidone (PVP) assisted acid etching process. Colloidosomes with sizes of around 5-10 µm composed of single-layer tetrakaidecahedron building blocks (BBs) were synthesized for the first time. Au@Ga-soc-MOF nanocomposites with excellent catalytic properties were obtained.