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Vascular embolization provides an effective approach for the treatment of hemorrhage, aneurysms, and other vascular abnormalities. However, current embolic materials, such as metallic coils and liquid embolic agents, are limited by their inability to provide safe, consistent, and controlled embolization. Here, we report an injectable hydrogel that can remain at the injection site and subsequently undergo in situ covalent crosslinking, leading to the formation of a dual-crosslinking network (DCN) hydrogel for endovascular embolization. The DCN hydrogel is simple to prepare, easy to deploy via needles and catheters, and mechanically stable at the target injection site, thereby avoiding embolization of nontarget vessels. It possesses efficient hemostatic activity and good biocompatibility. The DCN hydrogel is also clearly visible under X-ray imaging, thereby allowing for targeted embolization. In vivo tests in a rabbit artery model demonstrates that the DCN hydrogel is effective in achieving immediate embolization of the target artery with long-term occlusion by inducing luminal fibrosis. Collectively, the DCN hydrogel provides a viable, biocompatible, and cost-effective alternative to existing embolic materials with clinical translation potential for endovascular embolization.

The long-term success of endovascular intervention has long been overshadowed by vessel re-occlusion, also known as restenosis. Mainstream anti-restenotic devices, such as drug-eluting stent (DES) and drug-coated balloon (DCB), were recently shown with suboptimal performances and life-threatening complications, thereby underpinning the urgent need for alternative strategies with enhanced efficacy and safety profile. In our current study, we engineered a multimodal nanocluster formed by self-assembly of unimolecular nanoparticles and surface coated with platelet membrane, specifically tailored for precision drug delivery in endovascular applications. More specifically, it incorporates the combined merits of platelet membrane coating (lesion targetability and biocompatibility), reactive oxygen species (ROS)-detonable “cluster-bomb” chemistry (to trigger the large-to-small size transition at the target site, thereby achieving longer circulation time and higher tissue penetration), and sustained drug release. Using RVX-208 (an emerging anti-restenotic drug under clinical trials) as the model payload, we demonstrated the superior performances of our nanocluster over conventional poly(lactic-co-glycolic acid) (PLGA) nanoparticle. In cultured vascular smooth muscle cell (VSMC), the drug-loaded nanocluster induced effective inhibition of proliferation and protective gene expression (e.g., APOA-I) with a significantly reduced dosage of RVX-208 (1 μM). In a rat model of balloon angioplasty, intravenous injection of Cy5.5-tagged nanocluster led to greater lesion targetability, improved biodistribution, and deeper penetration into injured vessel walls featuring enriched ROS. Moreover, in contrast to either free drug solution or drug-loaded PLGA nanoparticle formulation, a single injection with the drug-loaded nanocluster (10 mg/kg of RVX-208) was sufficient to substantially mitigate restenosis. Additionally, this nanocluster also demonstrated biocompatibility according to in vitro cytotoxicity assay and in vivo histological and tissue qPCR analysis. Overall, our multimodal nanocluster offers improved targetability, tissue penetration, and ROS-responsive release over conventional nanoparticles, therefore making it a highly promising platform for development of next-generation endovascular therapies.

CRISPR genome editing has demonstrated great potential to treat the root causes of many genetic diseases, including central nervous system (CNS) disorders. However, the promise of brain-targeted therapeutic genome editing relies on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which represents a substantial challenge in the development of CRISPR therapeutics. In this study, we created a library of GSH-responsive silica nanocapsules (SNCs) and screened them for brain targeting via systemic delivery of nucleic acids and CRISPR genome editors.In vivostudies demonstrated that systemically delivered SNCs conjugated with glucose and RVG peptide under glycemic control can efficiently bypass the intact BBB, enabling brain-wide delivery of various biologics (mRNA, Cas9 mRNA/sgRNA, and Cas9/sgRNA ribonucleoprotein) targeting both exogenous genes (i.e., Ai14 stop cassette) and disease-relevant endogenous genes (i.e.,AppandThgenes) in Ai14 reporter mice and wild-type mice, respectively. In particular, we observed up to 28% neuron editing via systemic delivery of Cre mRNA in Ai14 mice, up to 6.1% amyloid precursor protein (App) gene editing (resulting in 19.1% reduction in the expression level of intact APP), and up to 3.9% tyrosine hydroxylase (Th) gene editing (resulting in 30.3% reduction in the expression level of TH) in wild-type mice. This versatile SNC nanoplatform may offer a novel strategy for the treatment of CNS disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease.

The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells. An imidazole-containing component was incorporated into the SNP to enhance the endosomal escape capability. The SNP can deliver various cargos, including nucleic acids (e.g., DNA and mRNA) and CRISPR genome editors (e.g., Cas9/sgRNA ribonucleoprotein (RNP), and RNP with donor DNA) with excellent efficiency and biocompatibility. The SNP surface can be PEGylated and functionalized with different targeting ligands. In vivo studies showed that subretinally injected SNP conjugated with all-trans-retinoic acid (ATRA) and intravenously injected SNP conjugated with GalNAc can effectively deliver mRNA and RNP to murine retinal pigment epithelium (RPE) cells and liver cells, respectively, leading to efficient genome editing. Overall, the SNP is a promising nanoplatform for various applications including gene therapy and genome editing.

Genome editing of somatic cells via clustered regularly interspaced short palindromic repeats (CRISPR) offers promise for new therapeutics to treat a variety of genetic disorders, including neurological diseases. However, the dense and complex parenchyma of the brain and the post-mitotic state of neurons make efficient genome editing challenging. In vivo delivery systems for CRISPR-Cas proteins and single guide RNA (sgRNA) include both viral vectors and non-viral strategies, each presenting different advantages and disadvantages for clinical application. We developed non-viral and biodegradable PEGylated nanocapsules (NCs) that deliver preassembled Cas9-sgRNA ribonucleoproteins (RNPs). Here, we show that the RNP NCs led to robust genome editing in neurons following intracerebral injection into the mouse striatum. Genome editing was predominantly observed in medium spiny neurons (>80%), with occasional editing in cholinergic, calretinin, and parvalbumin interneurons. Glial activation was minimal and was localized along the needle tract. Our results demonstrate that the RNP NCs are capable of safe and efficient neuronal genome editing in vivo.SIGNIFICANCE STATEMENTModifying the DNA of cells in the brain could present opportunities for new treatments of neurological diseases. In this report, we describe a nanocapsule system designed to deliver the elements needed to modify the DNA of brain cells, also known as genome editing. These nanocapsules are created by chemically encapsulating the genome editing components, such that the nanocapsules are stable when prepared and biodegradable to release their payload upon entering cells. When injected into the mouse brain, our research shows that the nanocapsules lead to safe and efficient editing of DNA in neurons.

Leber Congenital Amaurosis (LCA16) is a progressive vision loss disorder caused by point mutations in the KCNJ13 gene, which encodes an inward-rectifying potassium channel, Kir7.1. A nonsense mutation, W53X (c.158G>A), leads to premature truncation of the protein, which disrupts K+ conductance and makes retinal pigmented epithelium (RPE) non-functional. While there are no current treatments for LCA16, here we explore CRISPR base editing as a strategy to correct the single base pair pathogenic variant. We show that silica nanoparticle (SNC)-mediated delivery of an adenine base editor (ABE8e) mRNA and single-guide RNA can precisely and efficiently correct the KCNJ13W53X mutation to restore Kir7.1 channel function in an induced pluripotent stem cell-derived RPE (iPSC-RPE) model of LCA16, as well as in patient-derived fibroblasts and in a new LCA16 mouse model. We observed a higher editing efficiency in LCA16 patient-derived fibroblasts (47.38% ± 1.02) than in iPSC-RPE (16.90% ± 1.58) with no detectable off-target editing. The restored channel function in the edited cells resulted in a phenotype comparable to wild-type cells, suggesting the possibility that this treatment could restore vision in LCA16 patients. Injection of ABE8e-carrying SNCs decorated with all-trans retinoic acid (ATRA) ligand into the subretinal space in LCA16 mice showed specific delivery only to RPE and resulted in gene correction in approximately 10% of RPE cells that received the editing machinery. We observed marginal recovery of electroretinogram (ERG) following correction of the W53X allele at the injection site with no further degeneration of RPE. These findings provide a foundation and a proof-of-concept to transition from bench to bedside and support its further development for treating pediatric blindness using a safer mode of SNC-mediated delivery of base editors.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled—along with validated datasets—into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit—and the knowledge generated by its applications—as a means to accelerate the clinical development of new therapies for a wide range of conditions., This Perspective discusses how the Somatic Cell Genome Editing Consortium aims to accelerate the implementation of safe and effective genome-editing therapies in the clinic.

Occlusion of blood vessel caused by thrombus is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombus can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (H(2)O(2))-scavenging ability. Inspired by the abundance of H(2)O(2) and the active thrombus-targeting property of platelets, a H(2)O(2)-responsive platelet membrane-cloaked argatroban-loaded polymeric nanoparticle (PNP(Arg)) was developed for thrombus therapy. Poly(vanillyl alcohol-co-oxalate) (PVAX), a H(2)O(2)-degradable polymer, was synthesized to form an argatroban-loaded nanocore, which was further coated with platelet membrane. The PNP(Arg) can effectively target the blood clots due to the thrombus-homing property of the cloaked platelet membrane, and subsequently exert combined H(2)O(2)-scavenging effect via the H(2)O(2)-degradable nanocarrier polymer and antithrombotic effect via argatroban, the released payload. The PNP(Arg) effectively scavenged H(2)O(2) and protected cells from H(2)O(2)-induced cellular injury in RAW 264.7 cells and HUVECs. The PNP(Arg) rapidly targeted the thrombosed vessels and remarkably suppressed thrombus formation, and the levels of H(2)O(2) and inflammatory cytokine in the ferric chloride-induced carotid arterial thrombosis mouse model. Safety assessment indicated good biocompatibility of the PNP(Arg). Taken together, the biomimetic PNP(Arg) offers multifunctionalities including thrombus-targeting, antioxidation, and H(2)O(2)-stimulated antithrombotic action, thereby making it a promising therapeutic nanomedicine for thrombosis diseases.

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) may offer new therapeutics for genetic diseases through gene disruption via nonhomologous end joining (NHEJ) or gene correction via homology-directed repair (HDR). However, clinical translation of CRISPR technology is limited by the lack of safe and efficient delivery systems. Here, facilely fabricated pH-responsive polymer nanoparticles capable of safely and efficiently delivering Cas9 ribonucleoprotein alone (termed NHEJ-NP, diameter = 29.4 nm), or together with donor DNA (termed HDR-NP, diameter = 33.3 nm) are reported. Moreover, intravenously, intratracheally, and intramuscularly injected NHEJ-NP induces efficient gene editing in mouse liver, lung, and skeletal muscle, respectively. Intramuscularly injected HDR-NP also leads to muscle strength recovery in a Duchenne muscular dystrophy mouse model. NHEJ-NP and HDR-NP possess many desirable properties including high payload loading content, small and uniform sizes, high editing efficiency, good biocompatibility, low immunogenicity, and ease of production, storage, and transport, making them great interest for various genome editing applications with clinical potentials.

Triboelectric nanogenerators (TENGs) with high-energy output and high flexibility and transparency are desirable for a number of applications including flexible and transparent wearable devices. Th...

Efficient delivery of hydrophilic drugs, nucleic acids, proteins, and any combination thereof is essential for various biomedical applications. Herein, we report a straightforward, yet versatile approach to efficiently encapsulate and deliver various hydrophilic payloads using a pH-responsive silica–metal–organic framework hybrid nanoparticle (SMOF NP) consisting of both silica and zeolitic imidazole framework (ZIF). This unique SMOF NP offers a high loading content and efficiency, excellent stability, and robust intracellular delivery of a variety of payloads, including hydrophilic small molecule drugs (e.g., doxorubicin hydrochloride), nucleic acids (e.g., DNA and mRNA), and genome-editing machineries (e.g., Cas9-sgRNA ribonucleoprotein (RNP), and RNP together with donor DNA (e.g., RNP + ssODN)). The superior drug delivery/gene transfection/genome-editing efficiencies of the SMOF NP are attributed to its pH-controlled release and endosomal escape capabilities due to the proton sponge effect enabled by the imidazole moieties in the SMOF NPs. Moreover, the surface of the SMOF NP can be easily customized (e.g., PEGylation and ligand conjugation) via various functional groups incorporated into the silica component. RNP-loaded SMOF NPs induced efficient genome editing in vivo in murine retinal pigment epithelium (RPE) tissue via subretinal injection, providing a highly promising nanoplatform for the delivery of a wide range of hydrophilic payloads.

Visual Abstract, Highlights • Drug-eluting stents impede neointimal smooth muscle cell hyperplasia but exacerbate endothelial cell dysfunction and thrombogenicity. It has been a challenge to identify a common target to inhibit both. Findings in this study suggest PERK as such a target. • A PERK inhibitor administered either via an endovascular (in biomimetic nanocarriers) or perivascular (in hydrogel) route effectively mitigated neointimal hyperplasia in rats. • Oral gavage of the PERK inhibitor partially preserved the normal blood flow in a mouse model of induced thrombosis. • Dampening PERK activity inhibited STAT3 while activating SRF in smooth muscle cells, and also reduced prothrombogenic tissue factor and growth impairment of endothelial cells., Summary Developing endothelial-protective, nonthrombogenic antirestenotic treatments has been a challenge. A major hurdle to this has been the identification of a common molecular target in both smooth muscle cells and endothelial cells, inhibition of which blocks dysfunction of both cell types. The authors’ findings suggest that the PERK kinase could be such a target. Importantly, PERK inhibition mitigated both restenosis and thrombosis in preclinical models, implicating a low-thrombogenic antirestenotic paradigm.

An arch-structured triboelectric nanogenerator (TENG) was developed using nanofibrous poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) and nylon 6,6 (PA) membranes as the triboelectric pair and conductive fabrics as the electrodes. The nanofibrous microstructure and tribopolarity differences between the two triboelectric layers endow the TENG with outstanding triboelectric output performances, including an open-circuit voltage of 141.6 V and a short-circuit current of 20.4 μA. A maximum power density of 31.96 W m−2 was achieved at a load resistance of 106 Ω. The arch-structured TENG with such a high-power density has the ability to power portable small electronics, such as light-emitting-diodes (LEDs), liquid crystal displays (LCDs) and calculators. A self-powered sensing system was also fabricated using an arch-structured TENG and a signal processing circuit. The self-powered sensing system can readily detect the triboelectric signal generated by finger pressing and can effectively switch small electronics (e.g., an LED and a small motor) on and off. In addition, a TENG-based calculator was fabricated using 16 separate arch-structured TENGs that acted as the function keys of the calculator. Through real-time communication between a TENG-based calculator, a signal processing circuit and a computer, the TENG-based calculation system is able to complete the mathematical calculation process after the corresponding function keys were pressed. Therefore, an arch-structured TENG can not only power portable electronics, but also function as self-powered sensors in human-machine communication.

Genome editing of somatic cells via clustered regularly interspaced short palindromic repeats (CRISPR) offers promise for new therapeutics to treat a variety of genetic disorders, including neurological diseases. However, the dense and complex parenchyma of the brain and the post-mitotic state of neurons make efficient genome editing challenging. In vivo delivery systems for CRISPR-Cas proteins and single guide RNA (sgRNA) include both viral vectors and non-viral strategies, each presenting different advantages and disadvantages for clinical application. We developed non-viral and biodegradable PEGylated nanocapsules (NCs) that deliver preassembled Cas9-sgRNA ribonucleoproteins (RNPs). Here, we show that the RNP NCs led to robust genome editing in neurons following intracerebral injection into the healthy mouse striatum. Genome editing was predominantly observed in medium spiny neurons (80%), with occasional editing in cholinergic, calretinin, and parvalbumin interneurons. Glial activation was minimal and was localized along the needle tract. Our results demonstrate that the RNP NCs are capable of safe and efficient neuronal genome editing in vivo.

Ultrasonic energy harvesting technologies have gained much attention for biomedical applications due to their several desirable features including low-energy attenuation and strong penetration capability. In this work, flexible piezoelectric poly(vinylidenefluoride

Radiation therapy (RT) activates an in situ vaccine effect when combined with immune checkpoint blockade (ICB), yet this effect may be limited because RT does not fully optimize tumor antigen presentation or fully overcome suppressive mechanisms in the tumor-immune microenvironment. To overcome this, we develop a multifunctional nanoparticle composed of polylysine, iron oxide, and CpG (PIC) to increase tumor antigen presentation, increase the ratio of M1:M2 tumor-associated macrophages, and enhance stimulation of a type I interferon response in conjunction with RT. In syngeneic immunologically “cold” murine tumor models, the combination of RT, PIC, and ICB significantly improves tumor response and overall survival resulting in cure of many mice and consistent activation of tumor-specific immune memory. Combining RT with PIC to elicit a robust in situ vaccine effect presents a simple and readily translatable strategy to potentiate adaptive anti-tumor immunity and augment response to ICB or potentially other immunotherapies.

The CRISPR–Cas9 system is a powerful tool for genome editing, which can potentially lead to new therapies for genetic diseases. Up to date, various viral and non-viral delivery systems have been developed for the delivery of CRISPR-Cas9 in vivo. However, spatially and temporally controlled genome editing is needed to enhance the specificity in organs/tissues and minimize the off-target effects of editing. In this review, we summarize the state-of-the-art non-viral vectors that exploit external stimuli (i.e., light, magnetic field, and ultrasound) for spatially and temporally controlled genome editing and their in vitro and in vivo applications.

Sepsis is a life-threatening organ dysfunction responsible for nearly 270,000 deaths annually in the United States alone. Nicotinamide adenine dinucleotide (NAD

A double-network nanogel, composed of a silane-cross-linked polyethylenimine (PEI) network (i.e., PEI-S) and a pH-responsive poly(2-(hexamethyleneimino) ethyl methacrylate) (PC7A) polymer, was developed for efficient DNA transfection. The chemical cross-linking and hydrophobic interactions in the two networks led to improved stability outside the cell and also pH-triggered intracellular release of DNA. The nanogel with an optimal PEI-S and PC7A weight ratio of 1.3:1 exhibited significantly higher transfection efficiency than Lipofectamine 2000 in multiple cell lines. The nanogel also possessed a small size with a hydrodynamic diameter of 55 nm, low cytotoxicity, and superior stability in serum-containing media. Moreover, besides the PEI-based gene delivery system, we have also demonstrated that addition of the PC7A polymer to several types of cationic polymers commonly used for gene delivery also led to significant transfection enhancement of the resulting nanoparticles, suggesting that the PC7A polymer may be a universal additive that can benefit versatile cationic polymer-based gene delivery systems.

To meet the energy demand for flexible and miniaturized green electronics, it is highly desirable to develop a portable, cost-effective, lightweight, and sustainable power source through a facile and environment friendly approach. Herein, we report a portable, flexible, and low-cost self-charging power system (SCPS) consisting of a paper-based triboelectric nanogenerator (P-TENG) with high output power density as the energy harvester and a paper-based supercapacitor (P-SC) with a great areal capacitance as the energy storage device. A cellulose paper/polypyrrole composite with a low sheet resistance of 7.8 Ω sq–1 replaced the conventional metal electrodes and positive friction material in the P-TENG, as well as the capacitive material in the P-SC. The portable SCPS is capable of driving various miniaturized electronics such as a temperature/humidity indicator, thus demonstrating its potential as a sustainable power source for flexible and miniaturized green electronics.

Delivery technologies for the CRISPR-Cas9 (CRISPR, clustered regularly interspaced short palindromic repeats) gene editing system often require viral vectors, which pose safety concerns for therapeutic genome editing1. Alternatively, cationic liposomal components or polymers can be used to encapsulate multiple CRISPR components into large particles (typically >100 nm diameter); however, such systems are limited by variability in the loading of the cargo. Here, we report the design of customizable synthetic nanoparticles for the delivery of Cas9 nuclease and a single-guide RNA (sgRNA) that enables the controlled stoichiometry of CRISPR components and limits the possible safety concerns in vivo. We describe the synthesis of a thin glutathione (GSH)-cleavable covalently crosslinked polymer coating, called a nanocapsule (NC), around a preassembled ribonucleoprotein (RNP) complex between a Cas9 nuclease and an sgRNA. The NC is synthesized by in situ polymerization, has a hydrodynamic diameter of 25 nm and can be customized via facile surface modification. NCs efficiently generate targeted gene edits in vitro without any apparent cytotoxicity. Furthermore, NCs produce robust gene editing in vivo in murine retinal pigment epithelium (RPE) tissue and skeletal muscle after local administration. This customizable NC nanoplatform efficiently delivers CRISPR RNP complexes for in vitro and in vivo somatic gene editing. Polymer nanocapsules, assembled around a ribonucleoprotein complex of Cas9 nuclease and a single-guide RNA, enable safe and efficient gene editing in vitro and in vivo.

Cellulose-derived materials have gained a lot of attention for applications in advanced electronics because they are abundant, low cost, lightweight, and sustainable. Herein, we report a paper-based triboelectric nanogenerator (P-TENG) using commercially available materials derived from cellulose by a facile and cost-effective approach. Print paper is used as the substrate, while crepe cellulose paper (CCP) paired with a nitrocellulose membrane (NCM) are used as the friction layers of the P-TENG. CCP and NCM have significantly different tribopolarities and microstructures (i.e., corrugated and porous structures for CPP and NCM, respectively), thereby yielding P-TENGs with outstanding triboelectric performance. For instance, we have demonstrated P-TENGs with an output voltage and current of 196.8 V and 31.5 μA, respectively, a high power density of 16.1 W/m2, and a robust durability of more than 10,000 cycles. The P-TENGs, as a sustainable power source, can power various electronic devices. Moreover, their great potential applications in self-powered sensing and human–machine interfaces have been demonstrated. Human motion, like a finger touch, can be detected by the P-TENG. A keyboard based on an array of P-TENGs is able to achieve self-powered, real-time communication between a Paper Piano and a computer. This study not only combines the advantages of CCP and NCM to produce high-performance P-TENGs, but also demonstrates the feasibility of using commercially available products to prepare green and sustainable electronics.

Gene therapy holds great promise for various medical and biomedical applications. Nonviral gene delivery systems formed by cationic polymer and nucleic acids (e.g., polyplexes) have been extensively investigated for targeted gene therapy; however, their in vitro and in vivo stability is affected by both their intrinsic properties such as chemical compositions (e.g., polymer molecular weight and structure, and N/P ratio) and a number of environmental factors (e.g., shear stress during circulation in the bloodstream, interaction with the serum proteins, and physiological ionic strength). In this review, we surveyed the effects of a number of important intrinsic and environmental factors on the stability of polymeric gene delivery systems, and discussed various strategies to enhance the stability of polymeric gene delivery systems, thereby enabling efficient gene delivery into target cells. Future opportunities and challenges of polymeric nucleic acid delivery nanosystems were also briefly discussed.

To fulfill the increasing demand for radiofrequency (RF) wireless communication capacity for epidermal electronics, stretchable integrated circuits (ICs) in the gigahertz (GHz) range are desirable. Lumped RF inductors, as a key component in RFICs, typically dominate a large portion of the circuit/chip area and therefore make such inductors mechanically stretchable is critical for GHz-frequency stretchable RFICs. Most of the reported stretchable inductors operate in the MHz frequency range. The only GHz stretchable inductor shows a quality factor of about 2, limiting its potential RF applications. Here, stretchable inductors with a high quality factor of Q > 12.6 and resonance operation frequency of fres > 11.6 GHz are demonstrated by combining microspirals with stretchable structures, overcoming all of the shortcomings of previous demonstrations. Furthermore, a stretchable 1.5-2.6 GHz filter with a peak insertion loss of -2.3 dB at 1.8 GHz is developed, showing negligible performance changes under stretching or on the skin to demonstrate the utility in practical wireless applications like GSM and Bluetooth (2.45 GHz) bands. The demonstrations can facilitate multiple GHz epidermal RFICs in the future.

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. Here we developed a new modality of directly "painting" drug-loaded unimolecular micelles (UM) to the adventitia thus obviating the need for a hydrogel. To render tissue adhesion, we generated amine-reactive unimolecular micelles with N-hydroxysuccinimide ester (UM-NHS) terminal groups to form stable amide bonds with the adventitia. To test periadventitial application, we either soaked balloon-injured rat carotid arteries in crosslinked UM-NHS (Mode-1) or non-crosslinked UM-NHS (Mode-2), or painted the vessel surface with non-crosslinked UM-NHS (Mode-3). The UM-NHS were loaded with or without a model drug (rapamycin) known to be IH inhibitory. We found that Mode-1 produced a marked IH-mitigating drug effect but also caused severe tissue damage. Mode-2 resulted in lower tissue toxicity yet less drug effect on IH. However, the painting method, Mode-3, demonstrated a pronounced therapeutic effect (75% inhibition of IH) without obvious toxicity. In summary, we present a simple painting modality of periadventitial local drug delivery using tissue-adhesive UM. Given the robust IH-abating efficacy and low tissue toxicity, this prototype merits further development towards an effective anti-stenosis therapy suitable for open vascular reconstructions.

Scaffold microfabrication strategies for high-density, layered, and organized photoreceptor cell replacement are presented., Polymeric scaffolds are revolutionizing therapeutics for blinding disorders affecting the outer retina, a region anatomically and functionally defined by light-sensitive photoreceptors. Recent engineering advances have produced planar scaffolds optimized for retinal pigment epithelium monolayer delivery, which are being tested in early-stage clinical trials. We previously described a three-dimensional scaffold supporting a polarized photoreceptor monolayer, but photoreceptor somata typically occupy multiple densely packed strata to maximize light detection. Thus, patients with severe photoreceptor degeneration are expected to extract greater benefits from higher-density photoreceptor delivery. Here, we describe the microfabrication of a biodegradable scaffold patterned for high-density photoreceptor replacement. The “ice cube tray” structure optimizes mechanical properties and cell-to-biomaterial load, enabling production of a multicellular photoreceptor layer designed for outer retinal reconstruction. Our approach may also be useful in the production of a multitude of micro- and nanoscale structures for multilayered cell delivery in other tissues.

Thrombosis is a principle cause of various life-threatening cardiovascular diseases. However, current antithrombotic treatments using drugs only offer limited efficacy due to short half-life, low targeting ability to the thrombus site, and unexpected bleeding complications. Taking into account of the biological characteristics of thrombus including upregulation of hydrogen peroxide (H(2)O(2)) and abundance of fibrin, we engineered a H(2)O(2)-responsive nanocarrier for thrombus-targeting delivery of an antithrombotic agent (i.e., tirofiban). The nanocarrier was composed of a drug-conjugated dextran nanocore and a red blood cell (RBC) membrane shell, and its surface was functionalized with a fibrin-targeting peptide, CREKA. Tirofiban was conjugated to dextran through a H(2)O(2)-cleavable phenylboronic ester linkage. The fibrin-targeting RBC membrane-cloaked dextran-tirofiban conjugate nanoparticles (i.e., T-RBC-DTC NPs) can scavenge H(2)O(2) and provide controlled release of tirofiban to achieve site-specific antithrombotic effects. In RAW 264.7 cells and HUVECs, the T-RBC-DTC NPs effectively scavenged H(2)O(2) and protected cells from H(2)O(2)-induced cytotoxicity. In the ferric chloride-induced carotid thrombosis mouse model, the T-RBC-DTC NPs efficiently accumulated at the injured carotid artery and exhibited significantly enhanced antithrombotic activity compared to free drug. The T-RBC-DTC NPs also exhibited good biocompatibility according to histology analysis. Overall, our results indicated that this bioengineered nanocarrier offers a promising therapeutic strategy for thrombotic disorders.

Crosslinked polymer nanocapsules (CPNCs) are hollowed nanoparticles with network-like polymeric shells stabilized by primary bonds. CPNCs have drawn broad and significant interests as nanocarriers for biomedical applications in recent years. As compared with conventional polymeric nanoparticles systems without cavity and/or crosslinking architectures, CPNCs possess significant biomedical relevant advantages, including (a) superior structural stability against environmental conditions, (b) high loading capacity and ability for region-specific loading of multiple cargos, (c) tuneable cargo release rate via crosslinking density, and (d) high specific surface area to facilitate surface adsorption, modification, and interactions. With appropriate base polymers and crosslinkages, CPNCs can be biocompatible and biodegradable. While CPNC-based biomedical nanoplatforms can possess relatively stable physicochemical properties owing to their crosslinked architectures, various biomedically relevant stimuli-responsivities can be incorporated with them through specific structural designs. CPNCs have been studied for the delivery of small molecule drugs, genes, proteins, and other therapeutic agents. They have also been investigated as diagnostic platforms for magnetic resonance imaging, ultrasound imaging, and optical imaging. Moreover, CPNCs have been utilized to carry both therapeutics and bioimaging agents for theranostic applications. This article reviews the therapeutic, diagnostic and theranostic applications of CPNCs, as well as the preparation of these CPNCs, reported in the past decade. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

Low-cost flexible microwave circuits with compact size and light weight are highly desirable for flexible wireless communication and other miniaturized microwave systems. However, the prevalent studies on flexible microwave electronics have only focused on individual flexible microwave elements such as transistors, inductors, capacitors, and transmission lines. Thinning down supporting substrate of rigid chip-based monolithic microwave integrated circuits has been the only approach toward flexible microwave integrated circuits. Here, we report a flexible microwave integrated circuit strategy integrating membrane AlGaN/GaN high electron mobility transistor with passive impedance matching networks on cellulose nanofibril paper. The strategy enables a heterogeneously integrated and, to our knowledge, the first flexible microwave amplifier that can output 10 mW power beyond 5 GHz and can also be easily disposed of due to the use of cellulose nanofibril paper as the circuit substrate. The demonstration represents a critical step forward in realizing flexible wireless communication devices., Though flexible microwave integrated circuits (MICs) are desirable for the construction of functional microwave amplifier circuits, realizing low cost III-V-based MMICs remains a challenge. Here, the authors report a heterogeneous integration strategy for the fabrication of flexible low-cost MICs.

An abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta that plagues millions. Its rupture incurs high mortality rates (~80-90%), pressing an urgent need for therapeutic methods to prevent this deadly outcome. Judiciously designed nanoparticles (NPs) have displayed a unique potential to fulfill this need. Aneurysms feature excessive inflammation and extracellular matrix (ECM) degradation. As such, typically inflammatory cells and exposed ECM proteins have been targeted with NPs for therapeutic, diagnostic, or theranostic purposes in experimental models. NPs have been used not only for encapsulation and delivery of drugs and biomolecules in preclinical tests, but also for enhanced imaging to monitor aneurysm progression in patients. Moreover, they can be readily modified with various molecules to improve lesion targeting, detectability, biocompatibility, and circulation time. This review updates on the progress, limitations, and prospects of NP applications in the context of AAA.

PURPOSE: Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascularization with reduced levels of vascular endothelial growth factor (VEGF) causing vaso-obliteration (Phase I), followed abnormal neovascularization from increased VEGF (Phase II). We hypothesized that intravitreal pro-angiogenic VEGF-A in microparticle form would promote earlier retinal revascularization in an oxygen-induced ischemic retinopathy (OIR) mouse model. MATERIALS AND METHODS: Wildtype mice (39) were exposed to 77% oxygen from postnatal day 7 (P7) to P12. VEGF-A(165)-loaded poly(lactic-co-glycolic acid) (PLGA) (n=15) or empty PLGA (n=14) microparticles were fabricated using a water-in-oil-in-water double emulsion method, and injected intravitreally at P13 into mice right eyes (RE). Left eyes (LE) were untreated. At P20, after retinal fluorescein angiography, vascular parameters were quantified. Retinal VEGF levels at P13 and flatmounts at P20 were performed separately. RESULTS: VEGF-A(165)-loaded microparticles had a mean diameter of 4.2 μm. with a loading level of 8.6 weight.%. Retinal avascular area was reduced in VEGF-treated RE (39.5 ± 9.0%) compared to untreated LE (52.6 ± 6.1%, P< 0.0001) or empty microparticle-treated RE (P< 0.001) and untreated LEs (P= 0.001). Retinal arteries in VEGF-treated RE were less tortuous than untreated LE (1.08 ± 0.05 vs. 1.18 ± 0.08, P< 0.001) or empty-microparticles-treated RE (P= 0.02). Retinal arterial tortuosity was similar in the LE of VEGF and empty microparticle-treated mice (P> 0.05). Retinal vein width was similar in VEGF-treated and empty microparticle-treated RE (P> 0.9), which were each less dilated than their contralateral LE (P< 0.01). VEGF levels were higher in P13 OIR mice than RA mice (P< 0.0001). Retinal flatmounts showed vaso-obliteration and neovascularization. CONCLUSIONS: Endogenous retinal VEGF is suppressed in OIR mice. Exogenous intravitreal VEGF-A(165)-loaded microparticles in OIR mice reduced retinal vaso-obliteration and accelerated recovery from vein dilation and arterial tortuosity. This may be beneficial in preventing Phase II ROP without systemic effects.

Gene therapy holds great promise for the treatment of many diseases, but clinical translation of gene therapies has been slowed by the lack of safe and efficient gene delivery systems. Here, we report two versatile redox-responsive polyplexes (i.e., crosslinked and non-crosslinked) capable of efficiently delivering a variety of negatively charged payloads including plasmid DNA (DNA), messenger RNA (mRNA), Cas9/gRNA ribonucleoprotein (RNP), and RNP-donor DNA complexes (S1mplex) without any detectable cytotoxicity. The key component of both types of polyplexes is a cationic poly(N,N’-bis(acryloyl)cystamine-co-triethylenetetramine) (p(BAC-TET)) polymer (a type of poly(N,N’-bis(acryloyl)cystamine-poly(aminoalkyl)) (PBAP) polymer) containing disulfide bonds in the backbone and bearing imidazole groups. This composition enables efficient encapsulation, cellular uptake, controlled endo/lysosomal escape, and cytosolic unpacking of negatively-charged payloads. To further enhance the stability of non-crosslinked PBAP polyplexes, adamantane (AD) and β-cyclodextrin (β-CD) were conjugated to the PBAP-based polymers. The crosslinked PBAP (CLPBAP) polyplexes formed by host–guest interaction between β-CD and AD were more stable than non-crosslinked PBAP polyplexes in the presence of polyanionic polymers such as serum albumin, suggesting enhanced stability in physiological conditions. Both crosslinked and non-crosslinked polyplexes demonstrated either similar or better transfection and genome editing efficiencies, and significantly better biocompatibility than Lipofectamine 2000, a commercially available state-of-the-art transfection agent that exhibits cytotoxicity.

Spatiotemporal control over the release or activation of biomacromolecules such as siRNA remains a significant challenge. Light-controlled release has gained popularity in recent years; however, a major limitation is that most photoactivable compounds/systems respond only to UV irradiation, but not near-infrared (NIR) light that offers a deeper tissue penetration depth and better biocompatibility. This paper reports a simple NIR-to-UV upconversion nanoparticle (UCNP)-based siRNA nanocarrier for NIR-controlled gene silencing. siRNA is complexed onto a NaYF4:Yb/Tm/Er UCNP through an azobenzene (Azo)–cyclodextrin (CD) host–guest interaction. The UV emission generated by the NIR-activated UCNP effectively triggers the trans-to-cis photoisomerization of azobenzene, thus leading to the release of siRNA due to unmatched host – guest pairs. The UCNP-siRNA complexes are also functionalized with PEG (i.e., UCNP-(CD/Azo)-siRNA/PEG NPs), targeting ligands (i.e., EGFR-specific GE11 peptide), acid-activatable cell-penetrating peptides (i.e., TH peptide), and imaging probes (i.e., Cy5 fluorophore). The UCNP-(CD/Azo)-siRNA/PEG NPs with both GE11 and TH peptides display a high level of cellular uptake and an excellent endosomal/lysosomal escape capability. More importantly, NIR-controlled spatiotemporal knockdown of GFP expression is successfully achieved in both a 2D monolayer cell model and a 3D multicellular tumor spheroid model. Thus, this simple and versatile nanoplatform has great potential for the selective activation or release of various biomacromolecules.

Finding new means to enhance the performance of triboelectric nanogenerators (TENGs) is an ongoing pursuit. We report a novel flexible TENG made of highly porous cellulose nanofibril (CNF)/polyethylenimine (PEI) aerogel film paired with polyvinylidene fluoride (PVDF) nanofiber mats that exhibits outstanding triboelectric outputs. Modifying CNF with PEI not only enhances the mechanical properties of the CNF/PEI aerogel, but also greatly improves the power density by 14.4 times due to the enhanced tribopositivity. The triboelectric performance is further improved by employing multiple layers of PVDF mats. The TENG made of the CNF/PEI aerogel paired with four layers of PVDF mats exhibited an 18.3 times and 97.6 times improvement in output voltage and power density, respectively, compared to the TENG made of one layer of PVDF mat. The peak output power density reached 13.3 W/m2 at a load resistance of 106 Ω. Furthermore, the novel TENG displays extraordinary sensitivity when used as a self-powered sensor. It can detect not only human motion like arm bending and footsteps, but also small forces like finger tapping, water dripping, and the vibration of the substrate it is attached to. Therefore, this study not only demonstrates a high performance TENG, but also provides new insights into the design, fabrication, and application of TENGs.