In Situ Forming of Nitric Oxide and Electric Stimulus for Nerve Therapy by Wireless Chargeable Gold Yarn-Dynamos.

Endogenous signals, namely nitric oxide (NO) and electrons, play a crucial role in regulating cell fate as well as the vascular and neuronal systems. Unfortunately, utilizing NO and electrical stimulation in clinical settings can be challenging due to NO's short half-life and the invasive electrodes required for electrical stimulation. Additionally, there is a lack of tools to spatiotemporally control gas release and electrical stimulation. To address these issues, an "electromagnetic messenger" approach that employs on-demand high-frequency magnetic field (HFMF) to trigger NO release and electrical stimulation for restoring brain function in cases of traumatic brain injury is introduced. The system comprises a NO donor (poly(S-nitrosoglutathione), pGSNO)-conjugated on a gold yarn-dynamos (GY) and embedded in an implantable silk in a microneedle. When subjected to HFMF, conductive GY induces eddy currents that stimulate the release of NO from pGSNO. This process significantly enhances neural stem cell (NSC) synapses' differentiation and growth. The combined strategy of using NO and electrical stimulation to inhibit inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury is demonstrated in vivo.

Sustained Release of Nitric Oxide-Mediated Angiogenesis and Nerve Repair by Mussel-Inspired Adaptable Microreservoirs for Brain Traumatic Injury Therapy.

Traumatic brain injury (TBI) triggers inflammatory response and glial scarring, thus substantially hindering brain tissue repair. This process is exacerbated by the accumulation of activated immunocytes at the injury site, which contributes to scar formation and impedes tissue repair. In this study, a mussel-inspired nitric oxide-release microreservoir (MINOR) that combines the features of reactive oxygen species (ROS) scavengers and sustained NO release to promote angiogenesis and neurogenesis is developed for TBI therapy. The injectable MINOR fabricated using a microfluidic device exhibits excellent monodispersity and gel-like self-healing properties, thus allowing the maintenance of its structural integrity and functionality upon injection. Furthermore, polydopamine in the MINOR enhances cell adhesion, significantly reduces ROS levels, and suppresses inflammation. Moreover, a nitric oxide (NO) donor embedded into the MINOR enables the sustained release of NO, thus facilitating angiogenesis and mitigating inflammatory responses. By harnessing these synergistic effects, the biocompatible MINOR demonstrates remarkable efficacy in enhancing recovery in mice. These findings benefit future therapeutic interventions for patients with TBI.

Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks.

Traumatic brain injury causes inflammation and glial scarring that impede brain tissue repair, so stimulating angiogenesis and recovery of brain function remain challenging. Here we present an adaptable conductive microporous hydrogel consisting of gold nanoyarn balls-coated injectable building blocks possessing interconnected pores to improve angiogenesis and recovery of brain function in traumatic brain injury. We show that following minimally invasive implantation, the adaptable hydrogel is able to fill defects with complex shapes and regulate the traumatic brain injury environment in a mouse model. We find that placement of this injectable hydrogel at peri-trauma regions enhances mature brain-derived neurotrophic factor by 180% and improves angiogenesis by 250% in vivo within 2 weeks after electromagnetized stimulation, and that these effects facilitate neuron survival and motor function recovery by 50%. We use blood oxygenation level-dependent functional neuroimaging to reveal the successful restoration of functional brain connectivity in the corticostriatal and corticolimbic circuits.

Marginative Delivery-Mediated Extracellular Leakiness and T Cell Infiltration in Lung Metastasis by a Biomimetic Nanoraspberry.

T lymphocytes infiltrate the most devastating metastatic tumors for immunotherapy, allowing the potential for tumor metastasis suppression. However, tumor heterogeneity often restricts the infiltration of immune cells and possesses immune privilege that leads to protection from the immune attack, especially for invading metastatic clusters. Here, an exosome-camouflaged nanoraspberry (RB@Exo) doubling as a metastases-targeting agent and T cell-infiltration inducer that delivers an anticancer drug and energy is reported. The RB@Exo integrated an exosome-derived margination effect, and density-mediated nanoparticle-induced extracellular leakiness (nanoEL) exhibited more than a 70% colocalization of the RB@Exo to metastatic tumors in the lung in vivo. The release of cancer cell-cell interactions at the metastasis via nanoEL also elicited the 10-fold infiltration of T lymphocytes. The synergy of the T cell infiltration and photolytic effects transported by the RB@Exo deep into the metastatic tumors effectively inhibited the tumor in 60 days when treated with a single alternating magnetic field (AMF).

Transdermal Composite Microneedle Composed of Mesoporous Iron Oxide Nanoraspberry and PVA for Androgenetic Alopecia Treatment.

The transdermal delivery of therapeutic agents amplifying a local concentration of active molecules have received considerable attention in wide biomedical applications, especially in vaccine development and medical beauty. Unlike oral or subcutaneous injections, this approach can not only avoid the loss of efficacy of oral drugs due to the liver's first-pass effect but also reduce the risk of infection by subcutaneous injection. In this study, a magneto-responsive transdermal composite microneedle (MNs) with a mesoporous iron oxide nanoraspberry (MIO), that can improve the drug delivery efficiency, was fabricated by using a 3D printing-molding method. With loading of Minoxidil (Mx, a medication commonly used to slow the progression of hair loss and speed the process of hair regrowth), MNs can break the barrier of the stratum corneum through the puncture ability, and control the delivery dose for treating androgenetic alopecia (AGA). By 3D printing process, the sizes and morphologies of MNs is able to be, easily, architected. The MIOs were embedded into the tip of MNs which can deliver Mx as well as generate mild heating for hair growth, which is potentially attributed by the expansion of hair follicle and drug penetration. Compared to the mice without any treatments, the hair density of mice exhibited an 800% improvement after being treated by MNs with MF at 10-days post-treatment.

Injectable DNA-architected nanoraspberry depot-mediated on-demand programmable refilling and release drug delivery.

Drug delivery depots boosting a local concentration of therapeutic agents have received great attention in clinical applications due to their low occurrence of side effects and high therapeutic efficacy. However, once the payload is exhausted, the local drug concentration will be lower than the therapeutic window. To address this issue, an injectable double-strand deoxyribonucleic acid (DNA)-architected nanoraspberry depot (DNR-depot) was developed that can refill doxorubicin (Dox, an anticancer drug) from the blood and remotely control drug release on demand. The large porous surface on a uniform nanoraspberry (NR) filled covalently with DNA serves as a Dox sponge-like refilling reservoir, and the NR serves as a magnetic electrical absorber. Via the strong affinity between Dox and DNA molecules, the refilling process of Dox can be achieved on DNR-depot both in vitro and in vivo. Upon high-frequency magnetic field (HFMF) treatment, the remotely triggered release of Dox is actuated by the dissociation of Dox and DNA molecules, facilitating an approximately 800% improvement in drug concentration at the tumor site compared to free Dox injection alone. Furthermore, the cycles of refilling and release can be carried out more than 3 times in vivo within 21 days. The combination of refilling and HFMF-programmable Dox release in tumors via DNR-depot can effectively inhibit tumor growth for 30 days.

Adaptable Microporous Hydrogels of Propagating NGF-Gradient by Injectable Building Blocks for Accelerated Axonal Outgrowth.

Injectable hydrogels in regeneration medicine can potentially mimic hierarchical natural living tissue and fill complexly shaped defects with minimally invasive implantation procedures. To achieve this goal, however, the versatile hydrogels that usually possess the nonporous structure and uncontrollable spatial agent release must overcome the difficulties in low cell-penetrative rates of tissue regeneration. In this study, an adaptable microporous hydrogel (AMH) composed of microsized building blocks with opposite charges serves as an injectable matrix with interconnected pores and propagates gradient growth factor for spontaneous assembly into a complex shape in real time. By embedding gradient concentrations of growth factors into the building blocks, the propagated gradient of the nerve growth factor, integrated to the cell-penetrative connected pores constructed by the building blocks in the nerve conduit, effectively promotes cell migration and induces dramatic bridging effects on peripheral nerve defects, achieving axon outgrowth of up to 4.7 mm and twofold axon fiber intensity in 4 days in vivo. Such AMHs with intrinsic properties of tunable mechanical properties, gradient propagation of biocues and effective induction of cell migration are potentially able to overcome the limitations of hydrogel-mediated tissue regeneration in general and can possibly be used in clinical applications.

The Penetrated Delivery of Drug and Energy to Tumors by Lipo-Graphene Nanosponges for Photolytic Therapy.

Delivery of drug and energy within responsive carriers that effectively target and accumulate in cancer cells promises to mitigate side effects and to enhance the uniquely therapeutic efficacy demanded for personalized medicine. To achieve this goal, however, these carriers, which are usually piled up at the periphery of tumors near the blood vessel, must simultaneously overcome the challenges associated with low tumor penetration and the transport of sufficient cargos to deep tumors to eradicate whole cancer cells. Here, we report a sponge-like carbon material on graphene nanosheet (graphene nanosponge)-supported lipid bilayers (lipo-GNS) that doubles as a photothermal agent and a high cargo payload platform and releases a burst of drug/energy (docetaxel (DTX) and gasified perfluorohexane (PFH)) and intense heat upon near-infrared irradiation. Ultrasmall lipo-GNS (40 nm) modified with a tumor-targeting protein that penetrates tumor spheroids through transcytosis exhibited a 200-fold increase in accumulation relative to a 270 nm variant of the lipo-GNS. Furthermore, a combination of therapeutic agents (DTX and PFH) delivered by lipo-GNS into tumors was gasified and released into tumor spheroids and successfully ruptured and suppressed xenograft tumors in 16 days without distal harm when subjected to a single 10 min near-infrared laser treatment. Moreover, no tumor recurrence was observed over 60 days post-treatment. This sophisticated lipo-GNS is an excellent delivery platform for penetrated, photoresponsive, and combined gasification/chemo-thermotherapy to facilitate tumor treatment and for use in other biological applications.

Nanohybrids of magnetic iron-oxide particles in hydrophobic organoclays for oil recovery.

Nanohybrids with magnetic iron-oxide nanoparticles (FeNPs) embedded in the multilayered silicate clay were synthesized by in situ Fe(2+)/Fe(3+) coprecipitation. The natural clay, sodium montmorillonite (Na(+)-MMT), was first modified with hydrophobic poly(oxypropylene)amine salts (POP at 2000 and 4000 g/mol M(w)). The two POP-intercalated organoclays, with a silicate interlayer expansion from 1.2 to 5.2 and 9.2 nm, respectively, are suitable for embedding FeNPs. The presence of POP organics in layered structure created the space for intercalating with FeNPs of 2-4 nm in diameter, observed by transmission electronic microscope. The synthesized nanohybrids of POP4000/MMT-FeNP was composed of 17% iron oxide and 51 wt % POP within the silicate basal spacing of 5.0 nm. In contrast, the lower molecular weight of POP2000 intercalated MMT failed to encapsulate FeNPs in a significant amount, but resulting a "crowding-out effect" that caused the silicate interlayer space to shrink from 5.2 to 1.8 nm because of the replacement of the POP salt by Fe(2+)/Fe(3+) ions. The synthesis required the use of high molecular weight POP4000 and low temperatures (<4 degrees C) for a better dispersion in the reaction medium. The presence of POP in the layered silicate facilitated a homogeneous POP/MMT in water, associating with Fe(2+)/Fe(3+) ions and spatially accommodating for the subsequently generated FeNPs. The synthesized nanostructure consisting of POP and FeNP could be used as a pollutant remedy because of its ability to adsorbing crude oil and it is maneuverable under an applied magnetism.

Synthesis of acrylic copolymers consisting of multiple amine pendants for dispersing pigment.

A class of acrylic copolymers with narrow molecular weight distribution from butyl methacrylate and glycidyl methacrylate comonomers via atom transfer radical polymerization was synthesized. Various types of polarities including hydroxyl-amines, glycols, and carboxylic acids were then grafted onto the oxirane side groups. The resultant comb-like copolymers with different polar pendants were tested for homogenizing a representative Yellow pigment in 1,6-hexanediol diacrylate medium. Specifically, the polyacrylates with 1,3-diamine pendants (7-10 multiplicity on each polymer strain) enabled to homogeneously disperse the pigment than the analogous copolymers with hydroxyl or carboxylic acid groups. Ultimately, the pigment dispersion with an average size of ca. 20 nm in diameter, high transmittance and low viscosity was achieved. Furthermore, the pigment dispersion was allowed to UV-cure into a film, and for the first time, the primary structures of the pigment particles (ca. 50 nm in diameter) were observed by transmission electronic microscope.