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Maintaining stable drug concentrations in the bloodstream is a challenge for injectable hydrophobic progestin contraceptives. This work investigates porous silicon dioxide (pSiO 2 ) microparticles as a delivery vehicle for progestins via melt-infiltration of drugs into the mesopores. The pSiO 2 is prepared through electrochemical anodization of single-crystalline silicon followed by thermal oxidation, yielding vertically oriented pores (≈50 nm diameter) with porosity varied (between 35-75%) to optimize drug loading and release. Among the progestins tested, etonogestrel and levonorgestrel (LNG) decompose near their melting points, preventing melt infiltration. However, addition of 20% cholesterol by mass suppresses the melting point of LNG sufficiently to enable loading without degradation. Mass loadings exceeding 50% (drug: drug + carrier) are achieved for segesterone acetate (SEG) and LNG, retaining drug crystallinity as confirmed by X-ray diffraction. In vitro, both SEG and LNG-loaded pSiO 2 display sustained drug release for up to 3 months, with reduced burst release, more constant steady-state concentrations, and a substantially reduced tail compared to pure LNG or SEG, or SEG loaded into pSiO 2 from a chloroform solution. In a pilot in vivo study, SEG-loaded pSiO 2 microparticles are well tolerated in 20-week-old female rats over a 25-week period, with no signs of toxicity., (© 2025 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Combination therapies using checkpoint inhibitors with immunostimulatory agonists have attracted great attention due to their synergistic therapeutic effects for cancer treatment. However, such combination immunotherapies require specific timing of doses to show sufficient antitumor efficacy. Sequential treatment usually requires multiple administrations of the individual drugs at specific time points, thus increasing the complexity of the drug regimen and compromising patient compliance. Here, we introduce an injectable porous silicon microparticle (pSiMP) for combination cancer immunotherapy where its multilayered nanopore structure was electrochemically programmed to achieve release of three distinct immunomodulatory drugs in the right sequence at the desired time. We find the optimal sequential treatment timeline of stimulator of interferon genes (STING) agonist, anti-OX40 antibody (aOX40), and anti-PD-1 antibody (aPD-1) for immunosuppressive tumors. We show that a single intratumoral injection of a cocktail of release-programmed pSiMPs coloaded with each antibody and a STING agonist significantly suppresses the tumor growth compared to conventional treatment involving sequential bolus injections, or an injection of pSiMPs configured to release all drugs at the same time, with no delay. With the timely release of immunomodulatory drugs, the programmable pSiMPs offer an effective treatment strategy for combination immunotherapy.

The organophosphate (OP)-hydrolyzing enzyme phosphotriesterase (PTE, variant L7ep-3a) immobilized within a partially oxidized mesoporous silicon nanoparticle cage is synthesized and the catalytic performance of the enzyme@nanoparticle construct for hydrolysis of a simulant, dimethyl p-nitrophenyl phosphate (DMNP), and the live nerve agent VX is benchmarked against the free enzyme. In a neutral aqueous buffer, the optimized construct shows a ≈2-fold increase in the rate of DMNP turnover relative to the free enzyme. Enzyme@nanoparticles with more hydrophobic surface chemistry in the interior of the pores show lower catalytic activity, suggesting the importance of hydration of the pore interior on performance. The enzyme@nanoparticle construct is readily separated from the neutralized agent; the nanoparticle is found to retain DMNP hydrolysis activity through seven decontamination/recovery cycles. The nanoparticle cage stabilizes the enzyme against thermal denaturing and enzymatic (trypsin) degradation conditions relative to free enzyme. When incorporated into a topical gel formulation, the PTE-loaded nanoparticles show high activity toward the nerve agent VX in an ex vivo rabbit skin model. In vitro acetylcholinesterase (AChE) assays in human blood show that the enzyme@nanoparticle construct decontaminates VX, preserving the biological function of AChE when exposed to an otherwise incapacitating dose., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The sensitivity and responsiveness of living cells to environmental changes are enabled by dynamic protein structures, inspiring efforts to construct artificial supramolecular protein assemblies. However, despite their sophisticated structures, designed protein assemblies have yet to be incorporated into macroscale devices for real-life applications. We report a 2D crystalline protein assembly of C98/E57/E66 L-rhamnulose-1-phosphate aldolase ( CEE RhuA) that selectively blocks or passes molecular species when exposed to a chemical trigger. CEE RhuA crystals are engineered via cobalt(II) coordination bonds to undergo a coherent conformational change from a closed state (pore dimensions <1 nm) to an ajar state (pore dimensions ~4 nm) when exposed to an HCN(g) trigger. When layered onto a mesoporous silicon (pSi) photonic crystal optical sensor configured to detect HCN (g) , the 2D CEE RhuA crystal layer effectively blocks interferents that would otherwise result in a false positive signal. The 2D CEE RhuA crystal layer opens in selective response to low-ppm levels of HCN (g) , allowing analyte penetration into the pSi sensor layer for detection. These findings illustrate that designed protein assemblies can function as dynamic components of solid-state devices in non-aqueous environments., (© 2024. The Author(s).)

Nanomedicine is a growing field where development of novel organic and inorganic materials is essential to meet the complex requirements for drug delivery. This includes biocompatibility, suitability for surface modifications, biodegradability, and stability sufficient to carry a drug payload through various tissues for the desired timespan. Porous silicon nanoparticles (pSi NP) are shown to have several beneficial traits in drug delivery in addition to a porous structure to maximize drug loading. The conventional synthesis of pSi NP using electrochemical etching is costly, time-consuming and requires large quantities of highly toxic hydrofluoric acid (HF). As such this research attempted a novel method to address these limitations. Mesoporous silicon nanoparticles were prepared by centrifugal Chemical Vapor Deposition (cCVD) without the use of HF. This process generated aggregates consisting of multiple primary particles fused into each other, similar to snowballs fused together in a snow-lantern (snowball pyramid). Our results demonstrated that the cCVD Si particles were versatile in terms of surface chemistry, colloidal stability, degradability, minimization of acute in vitro toxicity, and modulation of drug release. Dynamic light scattering, scanning electron microscopy, and cryogenic nitrogen adsorption isotherm measurements confirmed the overall size (210 nm), morphology, and pore size (14-16 nm) of the prepared materials. Agglomeration in phosphate-buffered saline (PBS) was minimized by PEGylation by a two-step grafting procedure that employed a primary amine linker. Finally, the release rate of a model drug, hydrocortisone, was evaluated with both PEGylated and pristine particles. Conclusively, these snow-lantern cCVD Si particles do indeed appear suitable for drug delivery.

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 μg of MF/g of tissue vs. <10 μg of MF/g of tissue, respectively)., Competing Interests: Declaration of Competing Interest MJS is a scientific founder (SF), member of the Board of Directors (BOD), Advisory Board (AB), Scientific Advisory Board (SAB), acts as a paid consultant (PC) or has an equity interest (EI) in the following: Aivocode, Inc. (AB, EI); Bejing ITEC Technologies (SAB, PC); Lisata Therapeutics (SF, SAB, EI); Illumina (EI), Matrix Technologies (EI); NanoVision Bio (SAB, EI); Quanterix (EI), Spinnaker Biosciences, Inc. (SF, BOD, EI); TruTag Technologies (SAB, EI); and Well-Healthcare Technologies (SAB, PC). Although one or more of the grants that supported this research has been identified for conflict of interest management based on the overall scope of the project and its potential benefit to the companies listed, the research findings included in this publication may not necessarily relate to their interests. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The concept of using two-photon excitation in the NIR for the spatiotemporal control of biological processes holds great promise. However, its use for the delivery of nucleic acids has been very scarcely described and the reported procedures are not optimal as they often involve potentially toxic materials and irradiation conditions. This work prepares a simple system made of biocompatible porous silicon nanoparticles (pSiNP) for the safe siRNA photocontrolled delivery and gene silencing in cells upon two-photon excitation. PSiNP are linked to an azobenzene moiety, which possesses a lysine group (pSiNP@ICPES-azo@Lys) to efficiently complex siRNA. Non-linear excitation of the two-photon absorber system (pSiNP) followed by intermolecular energy transfer (FRET) to trans azobenzene moiety, result in the photoisomerization of the azobenzene from trans to cis and in the destabilization of the azobenzene-siRNA complex, thus inducing the delivery of the cargo siRNA to the cytoplasm of cells. Efficient silencing in MCF-7 expressing stable firefly luciferase with siRNAluc against luciferase is observed. Furthermore, siRNA against inhibitory apoptotic protein (IAP) leads to over 70% of MCF-7 cancer cell death. The developed technique using two-photon light allows a unique high spatiotemporally controlled and safe siRNA delivery in cells in few seconds of irradiation., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Evaluation of Gastrointestinal Stromal Tumors (GIST) during initial clinical staging, surgical intervention, and postoperative management can be challenging. Current imaging modalities ( e.g. , PET and CT scans) lack sensitivity and specificity. Therefore, advanced clinical imaging modalities that can provide clinically relevant images with high resolution would improve diagnosis. KIT is a tyrosine kinase receptor overexpressed on GIST. Here, the application of a specific DNA aptamer targeting KIT, decorated onto a fluorescently labeled porous silicon nanoparticle (pSiNP), is used for the in vitro & in vivo imaging of GIST. This nanoparticle platform provides high-fidelity GIST imaging with minimal cellular toxicity. An in vitro analysis shows greater than 15-fold specific KIT protein targeting compared to the free KIT aptamer, while in vivo analyses of GIST-burdened mice that had been injected intravenously (IV) with aptamer-conjugated pSiNPs show extensive nanoparticle-to-tumor signal co-localization (>90% co-localization) compared to control particles. This provides an effective platform for which aptamer-conjugated pSiNP constructs can be used for the imaging of KIT-expressing cancers or for the targeted delivery of therapeutics.

Aim: To evaluate an intravitreally injected nanoparticle platform designed to deliver VEGF-A siRNA to inhibit retinal neovascular leakage as a new treatment for proliferative diabetic retinopathy and diabetic macular edema. Materials & methods: Fusogenic lipid-coated porous silicon nanoparticles loaded with VEGF-A siRNA, and pendant neovascular integrin-homing iRGD, were evaluated for efficacy by intravitreal injection in a rabbit model of retinal neovascularization. Results: For 12 weeks post-treatment, a reduction in vascular leakage was observed for treated diseased eyes versus control eyes (p = 0.0137), with a corresponding reduction in vitreous VEGF-A. Conclusion: Fusogenic lipid-coated porous silicon nanoparticles siRNA delivery provides persistent knockdown of VEGF-A and reduced leakage in a rabbit model of retinal neovascularization as a potential new intraocular therapeutic.

The lack of drugs that target both disease progression and tissue preservation makes it difficult to effectively manage rheumatoid arthritis (RA). Here, we report a porous silicon-based nanomedicine that efficiently delivers an antirheumatic drug to inflamed synovium while degrading into bone-remodeling products. Methotrexate (MTX) is loaded into the porous silicon nanoparticles using a calcium silicate based condenser chemistry. The calcium silicate-porous silicon nanoparticle constructs (pCaSiNPs) degrade and release the drug preferentially in an inflammatory environment. The biodegradation products of the pCaSiNP drug carrier are orthosilicic acid and calcium ions, which exhibit immunomodulatory and antiresorptive effects. In a mouse model of collagen-induced arthritis, systemically administered MTX-loaded pCaSiNPs accumulate in the inflamed joints and ameliorate the progression of RA at both early and established stages of the disease. The disease state readouts show that the combination is more effective than the monotherapies.

Porous silicon (pSi) nanoparticles are loaded with Immunoglobulin A-2 (IgA2) antibodies, and the assembly is coated with pH-responsive polymers on the basis of the Eudragit family of enteric polymers (L100, S100, and L30-D55). The temporal release of the protein from the nanocomposite formulations is quantified following an in vitro protocol simulating oral delivery: incubation in simulated gastric fluid (SGF; at pH 1.2) for 2 h, followed by a fasting state simulated intestinal fluid (FasSIF; at pH 6.8) or phosphate buffer solution (PBS; at pH 7.4). The nanocomposite formulations display a negligible release in SGF, while more than 50% of the loaded IgA2 is released in solutions at a pH of 6.8 (FasSIF) or 7.4 (PBS). Between 21 and 44% of the released IgA2 retains its functional activity. A capsule-based system is also evaluated, where the IgA2-loaded particles are packed into a gelatin capsule and the capsule is coated with either EudragitL100 or EudragitS100 polymer for a targeted release in the small intestine or the colon, respectively. The capsule-based formulations outperform polymer-coated nanoparticles in vitro , preserving 45-54% of the activity of the released protein.

Peptide nucleic acids (PNAs) are a class of artificial oligonucleotide mimics that have garnered much attention as precision biotherapeutics for their efficient hybridization properties and their exceptional biological and chemical stability. However, the poor cellular uptake of PNA is a limiting factor to its more extensive use in biomedicine; encapsulation in nanoparticle carriers has therefore emerged as a strategy for internalization and delivery of PNA in cells. In this study, we demonstrate that PNA can be readily loaded into porous silicon nanoparticles (pSiNPs) following a simple salt-based trapping procedure thus far employed only for negatively charged synthetic oligonucleotides. We show that the ease and versatility of PNA chemistry also allows for producing PNAs with different net charge, from positive to negative, and that the use of differently charged PNAs enables optimization of loading into pSiNPs. Differently charged PNA payloads determine different release kinetics and allow modulation of the temporal profile of the delivery process. In vitro silencing of a set of specific microRNAs using a pSiNP-PNA delivery platform demonstrates the potential for biomedical applications.

Traumatic brain injury (TBI) is a major cause of disability and death among children and young adults in the United States, yet there are currently no treatments that improve the long-term brain health of patients. One promising therapeutic for TBI is brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and neuron survival. However, outstanding challenges to the systemic delivery of BDNF are its instability in blood, poor transport into the brain, and short half-life in circulation and brain tissue. Here, BDNF is encapsulated into an engineered, biodegradable porous silicon nanoparticle (pSiNP) in order to deliver bioactive BDNF to injured brain tissue after TBI. The pSiNP carrier is modified with the targeting ligand CAQK, a peptide that binds to extracellular matrix components upregulated after TBI. The protein cargo retains bioactivity after release from the pSiNP carrier, and systemic administration of the CAQK-modified pSiNPs results in effective delivery of the protein cargo to injured brain regions in a mouse model of TBI. When administered after injury, the CAQK-targeted pSiNP delivery system for BDNF reduces lesion volumes compared to free BDNF, supporting the hypothesis that pSiNPs mediate therapeutic protein delivery after systemic administration to improve outcomes in TBI.

Porous silicon (pSi) is an established porous material that offers ample opportunities for biosensor design thanks to its tunable structure, versatile surface chemistry, and large surface area. Nonetheless, its potential for electrochemical sensing is relatively unexplored. This study investigates layered carbon-stabilized pSi nanostructures with site-specific functionalities as an electrochemical biosensor. A double-layer nanostructure combining a top hydrophilic layer of thermally carbonized pSi (TCpSi) and a bottom hydrophobic layer of thermally hydrocarbonized pSi (THCpSi) is prepared. The modified layers are formed in a stepwise process, involving first an electrochemical anodization step to generate a porous layer with precisely defined pore morphological features, followed by deposition of a thin thermally carbonized coating on the pore walls via temperature-controlled acetylene decomposition. The second layer is then generated beneath the first by following the same two-step process, but the acetylene decomposition conditions are adjusted to deposit a thermally hydrocarbonized coating. The double-layer platform features excellent electrochemical properties such as fast electron-transfer kinetics, which underpin the performance of a TCpSi-THCpSi voltammetric DNA sensor. The biosensor targets a 28-nucleotide single-stranded DNA sequence with a detection limit of 0.4 pM, two orders of magnitude lower than the values reported to date by any other pSi-based electrochemical DNA sensor.

Bacterial infections are re-emerging as substantial threats to global health due to the limited selection of antibiotics that are capable of overcoming antibiotic-resistant strains. By deterring such mutations whilst minimizing the need to develop new pathogen-specific antibiotics, immunotherapy offers a broad-spectrum therapeutic solution against bacterial infections. In particular, pathology resulting from excessive immune response (i.e. fibrosis, necrosis, exudation, breath impediment) contributes significantly to negative disease outcome. Herein, we present a nanoparticle that is targeted to activated macrophages and loaded with siRNA against the Irf5 gene. This formulation is able to induce >80% gene silencing in activated macrophages in vivo, and it inhibits the excessive inflammatory response, generating a significantly improved therapeutic outcome in mouse models of bacterial infection. The versatility of the approach is demonstrated using mice with antibiotic-resistant Gram-positive (methicillin-resistant Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) muscle and lung infections, respectively. Effective depletion of the Irf5 gene in macrophages is found to significantly improve the therapeutic outcome of infected mice, regardless of the bacteria strain and type.

Tyrosine hydroxylase (TH) is the enzyme catalyzing the rate-limiting step in the synthesis of dopamine in the brain. Developing enzyme replacement therapies using TH could therefore be beneficial to patient groups with dopamine deficiency, and the use of nanocarriers that cross the blood-brain barrier seems advantageous for this purpose. Nanocarriers may also help to maintain the structure and function of TH, which is complex and unstable. Understanding how TH may interact with a nanocarrier is therefore crucial for the investigation of such therapeutic applications. This work describes the interaction of TH with porous silicon nanoparticles (pSiNPs), chosen since they have been shown to deliver other macromolecular therapeutics successfully to the brain. Size distributions obtained by dynamic light scattering show a size increase of pSiNPs upon addition of TH and the changes observed at the surface of pSiNPs by transmission electron microscopy also indicated TH binding at pH 7. As pSiNPs are negatively charged, we also investigated the binding at pH 6, which makes TH less negatively charged than at pH 7. However, as seen by thioflavin-T fluorescence, TH aggregated at this more acidic pH. TH activity was unaffected by the binding to pSiNPs most probably because the active site stays available for catalysis, in agreement with calculations of the surface electrostatic potential pointing to the most positively charged regulatory domains in the tetramer as the interacting regions. These results reveal pSiNPs as a promising delivery device of enzymatically active TH to increase local dopamine synthesis.

A one-dimensional photonic crystal is prepared from porous silicon (pSi) and impregnated with a chemically specific colorimetric indicator dye to provide a self-referenced vapor sensor for the selective detection of hydrogen fluoride (HF), hydrogen cyanide (HCN), and the chemical nerve agent diisopropyl fluorophosphate (DFP). The photonic crystal is prepared with two stop bands: one that coincides with the optical absorbance of the relevant activated indicator dye and the other in a spectrally "clear" region, to provide a reference. The inner pore walls of the pSi sample are then modified with octadecylsilane to provide a hydrophobic interior, and the indicator dye of interest is then loaded into the mesoporous matrix. Remote analyte detection is achieved by measurement of the intensity ratio of the two stop bands in the white light reflectance spectrum, which provides a means to reliably detect colorimetric changes in the indicator dye. Indicator dyes were chosen for their specificity for the relevant agents: rhodamine-imidazole (RDI) for HF and DFP, and monocyanocobinamide (MCbi) for HCN. The ratiometric readout allows detection of HF and HCN at concentrations (14 and 5 ppm, respectively) that are below their respective IDLH (immediately dangerous to life and health) concentrations (30 ppm for HF; 50 ppm for HCN); detection of DFP at a concentration of 114 ppb is also demonstrated. The approach is insensitive to potential interferents such as ammonia, hydrogen chloride, octane, and the 43-component mixture of VOCs known as EPA TO-14A, and to variations in relative humidity (20-80% RH). Detection of HF and HCN spiked into the complex mixture EPA TO-14A is demonstrated. The approach provides a general means to construct robust remote detection systems for chemical agents.

To acheive flexible polyurethane (PU) foam composites with stable electrical conductivity and high flame retardancy involved first coating of graphene oxide (GO) onto PU foam surfaces and then chemically reducing the GO with hydrazine to form reduced GO (RGO). The RGO-coated PU foam is then dipped into a solution containing silicone resin (SiR) and silica nano-particles and cured. The resulting composites (PU-RGO-SiR) show superior flame retardancy, thermal stability and mechanical stability relative to the PU starting materials or PU coated with either RGO or SiR alone. The electrical conductivity of the PU-RGO-SiR composites (as high as 118 S m -1 at room temperature) could almost be retained but with small loss of 9.5% of the original value after 150 cyclic compression. When the samples were subjected to a temperature range from -50 to 400 °C, the electrical conductivity could remain constant at -50 °C, 25 °C, 100 °C, 200 °C, and even at 300 °C and 400 °C; the electrical-conductivity exhibited mild vibration but the vibration range was not beyond 5.6%. Flame retardancy tests show that the limiting oxygen index (LOI) increases from 14.7% for the pure foam to 31.5% for PU-RGO-SiR, and the PU-RGO-SiR composites exhibit a 65% reduction in the peak heat release rate (pHRR) and a 30% reduction in total smoke release (TSR). Thus, stable electrically conductive and highly flame-retardant foam composites have potential applications even in a variety of harsh conditions like high temperature, flame, organic solvents, and external compression.

Mesoporous silica has attracted significant attention in the drug delivery area; however, impurities can be a source of toxicity. The current study used commercial microparticles produced at large scale in a well-controlled environment. Micrometer sized mesoporous silica particles were acquired through a commercial vendor and pore structures were characterized by SEM. The three silica particle formulations had a diameter of 15 micrometers and three different pore sizes of 10 nm, 30 nm, and 100 nm. The fourth formulation had particle size of 20-40 micrometers with 50 nm pores. Before in vivo tests, an in vitro cytotoxicity test was conducted with silicic acid, derived from the sol-gel particles, on EA.hy926 cells. Low concentration (2.5 µg/mL) of silicic acid showed no cytotoxicity; however, high concentration (25 µg/mL) was cytotoxic. In vivo intravitreal injection demonstrated that 15 um silica particles with 10 nm pore were safe in both rabbit and guinea pig eyes and the particles lasted in the vitreous for longer than two months. Formulations of with larger pores demonstrated variable localized vitreous cloudiness around the sol-gel particle depot and mild inflammatory cells in the aqueous humor. The incidence of reaction trended higher with larger pores (10 nm: 0%, 30 nm: 29%, 50 nm: 71%, 100 nm: 100%, p  < .0001, Cochran Armitage Trend Test). Sol-gel mesoporous silica particles have uniform particle sizes and well-defined pores, which is an advantage for implantation via a fine needle. Selected formulations may be used as an intraocular drug delivery system with proper loading and encapsulation.

Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO 2 ) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO 2 particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, p  < .05). Eyes pretreated with pSiO 2 -DNR + DEX exhibited the least GFAP activation (least square mean intensity mm -2 : Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, p  < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, p  < .05). The synergistic effect of a sustained release pSiO 2 -DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.

Organ-specific cell-penetrating peptides (CPPs) are a class of molecules that can be highly effective at delivering therapeutic cargoes, and they are currently of great interest in cancer treatment strategies. Herein, we describe a new CPP (amino acid sequence serine-isoleucine-tyrosine-valine, or SIWV) that homes to glioblastoma multiforme (GBM) brain tumor tissues with remarkable specificity in vitro and in vivo. The SIWV sequence was identified from an isoform of annexin-A3 (AA3H), a membrane-interacting human protein. The mechanism of intracellular permeation is proposed to follow a caveolin-mediated endocytotic pathway, based on in vitro and in vivo receptor inhibition and genetic knockdown studies. Feasibility as a targeting agent for therapeutics is demonstrated in a GBM xenograft mouse model, where porous silicon nanoparticles (pSiNPs) containing the clinically relevant anticancer drug SN-38 are grafted with SIWV via a poly-(ethylene glycol) (PEG) linker. The formulation shows enhanced in vivo targeting ability relative to a formulation employing a scrambled control peptide, and significant (P < 0.05) therapeutic efficacy relative to free SN-38 in the GBM xenograft animal model.

Scaffolds made from biocompatible polymers provide physical cues to direct the extension of neurites and to encourage repair of damaged nerves. The inclusion of neurotrophic payloads in these scaffolds can substantially enhance regrowth and repair processes. However, many promising neurotrophic candidates are excluded from this approach due to incompatibilities with the polymer or with the polymer processing conditions. This work provides one solution to this problem by incorporating porous silicon nanoparticles (pSiNPs) that are pre-loaded with the therapeutic into a polymer scaffold during fabrication. The nanoparticle-drug-polymer hybrids are prepared in the form of oriented poly(lactic- co -glycolic acid) nanofiber scaffolds. We test three different therapeutic payloads: bpV(HOpic), a small molecule inhibitor of phosphatase and tensin homolog (PTEN); an RNA aptamer specific to tropomyosin-related kinase receptor type B (TrkB); and the protein nerve growth factor (NGF). Each therapeutic is loaded using a loading chemistry that is optimized to slow the rate of release of these water-soluble payloads. The drug-loaded pSiNP-nanofiber hybrids release approximately half of their TrkB aptamer, bpV(HOpic), or NGF payload in 2, 10, and >40 days, respectively. The nanofiber hybrids increase neurite extension relative to drug-free control nanofibers in a dorsal root ganglion explant assay.

Synthetic DNA-based oligonucleotides are loaded into porous silicon nanoparticles (pSiNPs) and incorporated into nanofibers of poly(lactide-co-glycolide) (PLGA), poly-l-lactic acid (PLA), or polycaprolactone (PCL). The resulting hybrid nanofibers are characterized for their ability to release the functional oligonucleotide payload under physiologic conditions. Under temperature and pH conditions mimicking physiological values, the PLGA-based nanofibers release >80% of their DNA cargo within 5 days, whereas the PLA and PCL-based fibers require 15 days to release >80% of their cargo. The quantity of DNA released scales with the quantity of DNA-loaded pSiNPs embedded in the nanofibers; mass loadings of between 2.4 and 9.1% (based on mass of DNA-pSiNP construct relative to mass of polymer composite) are investigated. When a responsive DNA-based nanodevice (i.e. molecular beacon) is used as a payload, it retains its functionality during the release period, independent of the polymer used for the formation of the nanofibers.

Optical lenses are among the oldest technological innovations (3000 years ago) and they have enabled a multitude of applications in healthcare and in our daily lives. The primary function of optical lenses has changed little over time; they serve mainly as a light-collection (e.g. reflected, transmitted, diffracted) element, and the wavelength and/or intensity of the collected light is usually manipulated by coupling with various external optical filter elements or coatings. This generally results in losses associated with multiple interfacial reflections, and increases the complexity of design and construction. In this work we introduce a change in this paradigm, by integrating both light-shaping and image magnification into a single lens element using a moldless procedure that takes advantage of the physical and optical properties of mesoporous silicon (PSi) photonic crystal nanostructures. Casting of a liquid poly(dimethyl) siloxane (PDMS) pre-polymer solution onto a PSi film generates a droplet with contact angle that is readily controlled by the silicon nanostructure, and adhesion of the cured polymer to the PSi photonic crystal allows preparation of lightweight (10 mg) freestanding lenses (4.7 mm focal length) with an embedded optical component (e.g. optical rugate filter, resonant cavity, distributed Bragg reflector). Our fabrication process shows excellent reliability (yield 95%) and low cost and we expect our lens to have implications in a wide range of applications. As a proof-of-concept, using a single monolithic lens/filter element we demonstrate: fluorescence imaging of isolated human cancer cells with rejection of the blue excitation light, through a lens that is self-adhered to a commercial smartphone; shaping the emission spectrum of a white light emitting diode (LED) to tune the color from red through blue; and selection of a narrow wavelength band (bandwidth 5 nm) from a fluorescent molecular probe.

With the recent FDA approval of the first siRNA-derived therapeutic, RNA interference (RNAi)-mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA-mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Most current nanoparticle-based PET tracers are radiolabeled through metal chelators conjugated on the nanoparticle surface. Metal chelation usually requires sophisticated optimization and may impact the physical or chemical properties of nanoparticles, which leads to the changes in their distribution and pharmacokinetics in vivo. A chelator-free radiolabeling approach is thus highly desirable. Here, we report that zinc sulfide (ZnS) quantum dots (QDs) can be rapidly radiolabeled with 68Ga or 64Cu through cation exchange without chelators. The radiolabeling was accomplished in times as short as 5 min at 37 °C in aqueous solution, yielding a high labeling efficiency and radiochemical purity for both isotopes. Surface functionalization with targeting peptides was also readily achieved to enable or enhance the cellular uptake of QDs. In vivo PET imaging showed that 64Cu-labeled QDs had a much higher tumor uptake (7.3% ID g-1) than 64Cu-DOTA in a murine cancer model. Overall, this study presents a QD-based platform to achieve convenient and chelator-free radiolabeling, and improve PET imaging of solid tumors.

Despite the promise of ribonucleic acid interference therapeutics, the delivery of oligonucleotides selectively to diseased tissues in the body, and specifically to the cellular location in the tissues needed to provide optimal therapeutic outcome, remains a significant challenge. Here, key material properties and biological mechanisms for delivery of short interfering RNAs (siRNAs) to effectively silence target-specific cells in vivo are identified. Using porous silicon nanoparticles as the siRNA host, tumor-targeting peptides for selective tissue homing, and fusogenic lipid coatings to induce fusion with the plasma membrane, it is shown that the uptake mechanism can be engineered to be independent of common receptor-mediated endocytosis pathways. Two examples of the potential broad clinical applicability of this concept in a mouse xenograft model of ovarian cancer peritoneal carcinomatosis are provided: silencing the Rev3l subunit of polymerase Pol ζ to impair DNA repair in combination with cisplatin; and reprogramming tumor-associated macrophages into a proinflammatory state., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis of microribbons based on the assembly of porous silicon nanoparticles (pSiNPs) in a silica matrix is reported. The formation of these structures is driven by dissolution and reprecipitation of silica derived from the NPs upon drying of an aqueous colloidal dispersion. The process generates composite films that fracture into filaments due to geometric stresses associated with drying of the film on a curved surface. By controlling NP concentration, solvent, and temperature during the evaporation process, well-defined microribbons with a rectangular cross section of ∼25 × 100 microns and lengths on the order of 1 cm are formed. Partial thermal oxidation of the ribbons generates luminescent Si-SiO 2 core-shell composites, and complete oxidation generates porous SiO 2 ribbons with retention of the mesoporous nanostructure. The pores can be infiltrated with daunorubicin as a model drug, and the resulting material shows sustained release of the chemotherapeutic for more than 70 days.

Porous silicon photoluminescence is characterized by a broad emission band that displays unusually long (tens to hundreds of micro-seconds), wavelength-dependent emissive lifetimes. The photoluminescence is associated with quantum confinement of excitons in silicon nanocrystallites contained within the porous matrix, and the broad emission spectrum derives from the wide distribution of nanocrystallite sizes in the material. The longer emissive lifetimes in the ensemble of quantum-confined emitters correspond to the larger nanocrystallites, with their longer wavelengths of emission. The quenching of this photoluminescence by aromatic, redox-active molecules aminochrome (AMC), dopamine, adrenochrome, sodium anthraquinone-2-sulfonate, benzyl viologen dichloride, methyl viologen dichloride hydrate, and ethyl viologen dibromide is studied, and dynamic and static quenching mechanisms are distinguished by the emission lifetime analysis. Because of the dependence of the emission lifetime on emission wavelength from the silicon nanocrystallite ensemble, a pronounced blue shift is observed in the steady-state emission spectrum upon exposure to dynamic-type quenchers. Conversely, static-type quenching systems show uniform quenching across all emission wavelengths. Thus, the difference between static and dynamic quenching mechanisms is readily distinguished by ratiometric photoluminescence spectroscopy. The application of this concept to imaging of AMC, the oxidized form of the neurotransmitter dopamine that is of interest for its role in neurodegenerative diseases, is demonstrated. It is found that static electron acceptors result in no ratiometric contrast, while AMC shows a strong contrast, allowing ready visualization in a 2-D imaging experiment., Competing Interests: The authors declare the following competing financial interest(s): MJS holds an appointment as a High-Level Talent' at the Key Laboratory of Organosilicon Chemistry and Material Technology of Hangzhou Normal University, and he is a scientific founder of Spinnaker Biosciences, Inc., a member of the Board of Direc-tors, and has an equity interest in the company. Although one or more of the grants that supported this research has been iden-tified for conflict of interest management based on the overall scope of the project and its potential benefit to Spinnaker Biosci-ences, Inc., the research findings included in this particular publication may not necessarily relate to the interests of Spinnaker Biosciences, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

Silencing of aberrantly expressed microRNAs (miRNAs or miRs) has emerged as one of the strategies for molecular targeted cancer therapeutics. In particular, miR-21 is an oncogenic miRNA overexpressed in many tumors, including ovarian cancer. To achieve efficient administration of anti-miR therapeutics, delivery systems are needed that can ensure local accumulation in the tumor environment, low systemic toxicity, and reduced adverse side effects. In order to develop an improved anti-miR therapeutic agent for the treatment of ovarian cancer, a nanoformulation is engineered that leverages biodegradable porous silicon nanoparticles (pSiNPs) encapsulating an anti-miR-21 locked nucleic acid payload and displaying a tumor-homing peptide for targeted distribution. Targeting efficacy, miR-21 silencing, and anticancer activity are optimized in vitro on a panel of ovarian cancer cell lines, and a formulation of anti-miR-21 in a pSiNP displaying the targeting peptide CGKRK is identified for in vivo evaluation. When this nanoparticulate agent is delivered to mice bearing tumor xenografts, a substantial inhibition of tumor growth is achieved through silencing of miR-21. This study presents the first successful application of tumor-targeted anti-miR porous silicon nanoparticles for the treatment of ovarian cancer in a mouse xenograft model.

Macrophages play important and diverse roles during cancer progression. However, cancer therapies based on macrophage modulation are lacking in tools that can recognize and deliver therapeutic payloads to macrophages in a tumor-specific manner. As a result, treatments tend to interfere with normal macrophage functions in healthy organs. We previously identified a macrophage-binding peptide, termed CRV. Here, we show that upon systemic administration into tumor-bearing mice, CRV selectively homes to tumors, extravasates, and preferentially binds to macrophages within. CRV exhibits a higher affinity for tumor macrophages than for other cells in tumors or for other macrophage types elsewhere in the body. We further identified and validated retinoid X receptor beta (RXRB) as the CRV receptor. Intriguingly, although it is known as a nuclear receptor, RXRB shows a prominent cell surface localization that is largely restricted to tumor macrophages. Systemic administration of anti-RXRB antibodies also results in tumor-selective binding to macrophages similar to CRV. Lastly, we demonstrate the ability of CRV to improve the delivery of nano-carriers into solid tumors and macrophages within. In summary, we describe here a novel cell surface marker and targeting tools for tumor macrophages that may aid in future development of macrophage-modulatory cancer therapies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

With the advent of gene therapy, the development of an effective in vivo nucleotide-payload delivery system has become of parallel import. Fusogenic porous silicon nanoparticles (F-pSiNPs) have recently demonstrated high in vivo gene silencing efficacy due to its high oligonucleotide loading capacity and unique cellular uptake pathway that avoids endocytosis. The synthesis of F-pSiNPs is a multi-step process that includes: (1) loading and sealing of oligonucleotide payloads in the silicon pores; (2) simultaneous coating and sizing of fusogenic lipids around the porous silicon cores; and (3) conjugation of targeting peptides and washing to remove excess oligonucleotide, silicon debris, and peptide. The particle's size uniformity is characterized by dynamic light scattering, and its core-shell structure may be verified by transmission electron microscopy. The fusogenic uptake is validated by loading a lipophilic dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), into the fusogenic lipid bilayer and treating it to cells in vitro to observe for plasma membrane staining versus endocytic localizations. The targeting and in vivo gene silencing efficacies were previously quantified in a mouse model of Staphylococcus aureus pneumonia, in which the targeting peptide is expected to help the F-pSiNPs to home to the site of infection. Beyond its application in S. aureus infection, the F-pSiNP system may be used to deliver any oligonucleotide for gene therapy of a wide range of diseases, including viral infections, cancer, and autoimmune diseases.

We propose a rapid, one-pot method to generate photoluminescent (PL) mesoporous silicon nanoparticles (PSiNPs). Typically, mesoporous silicon (meso-PSi) films, obtained by electrochemical etching of monocrystalline silicon substrates, do not display strong PL because the silicon nanocrystals (nc-Si) in the skeleton are generally too large to display quantum confinement effects. Here we describe an improved approach to form photoluminescent PSiNPs from meso-PSi by partial oxidation in aqueous sodium borate (borax) solutions. The borax solution acts to simultaneously oxidize the nc-Si surface and to partially dissolve the oxide product. This results in reduction of the size of the nc-Si core into the quantum confinement regime, and formation of an insulating silicon dioxide (SiO 2 ) shell. The shell serves to passivate the surface of the silicon nanocrystals more effectively localizing excitons and increasing PL intensity. We show that the oxidation/dissolution process can be terminated by addition of excess citric acid, which changes the pH of the solution from alkaline to acidic. The process is monitored in situ by measurement of the steady-state PL spectrum from the PSiNPs. The measured PL intensity increases by 1.5- to 2-fold upon addition of citric acid, which we attribute to passivation of non-radiative recombination centers in the oxide shell. The measured PL quantum yield of the final product is up to 20%, the PL activation procedure takes <20 min, and the resulting material remains stable in aqueous dispersion for at least 1 day. The proposed phenomenological model explaining the process takes into account both pH changes in the solution and the potential increase in solubility of silicic acid due to interaction with sodium cations.

A nanoparticle system for systemic delivery of therapeutics is described, which incorporates a means of tracking the fate of the nanocarrier and its residual drug payload in vivo by photoluminescence (PL). Porous silicon nanoparticles (PSiNPs) containing the proapoptotic antimicrobial peptide payload, D [KLAKLAK] 2 , are monitored by measurement of the intrinsic PL intensity and the PL lifetime of the nanoparticles. The PL lifetime of the PSiNPs is on the order of microseconds, substantially longer than the nanosecond lifetimes typically exhibited by conventional fluorescent tags or by autofluorescence from cells and tissues; thus, emission from the nanoparticles is readily discerned in the time-resolved PL spectrum. It is found that the luminescence lifetime of the PSiNP host decreases as the nanoparticle dissolves in phosphate-buffered saline solution (37 °C), and this correlates with the extent of release of the peptide payload. The time-resolved PL measurement allows tracking of the in vivo fate of PSiNPs injected (via tail vein) into mice. Clearance of the nanoparticles through the liver, kidneys, and lungs of the animals is observed. The luminescence lifetime of the PSiNPs decreases with increasing residence time in the mice, providing a measure of half-life for degradation of the drug nanocarriers., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Photoacoustic (PA) imaging allows visualization of the physiology and pathology of tissues with good spatial resolution and relatively deep tissue penetration. The method converts near-infrared (NIR) laser excitation into thermal expansion, generating pressure transients that are detected with an acoustic transducer. Here, we find that the response of the PA contrast agent indocyanine green (ICG) can be enhanced 17-fold when it is sealed within a rigid nanoparticle. ICG encapsulated in particles composed of porous silicon (pSiNP), porous silica, or calcium silicate all show greater PA contrast relative to equivalent quantities of free ICG, with the pSiNPs showing the strongest enhancement. A liposomal formulation of ICG performs similar to free ICG, suggesting that a rigid host nanostructure is necessary to enhance ICG performance. The improved response of the nanoparticle formulations is attributed to the low thermal conductivity of the porous inorganic hosts and their ability to protect the ICG payload from photolytic and/or thermal degradation. The translational potential of ICG-loaded pSiNPs as photoacoustic probes is demonstrated via imaging of a whole mouse brain., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia.

Organic-inorganic hybrid perovskites have demonstrated tremendous potential for the next-generation electronic and optoelectronic devices due to their remarkable carrier dynamics. Current studies are focusing on polycrystals, since controlled growth of device compatible single crystals is extremely challenging. Here, the first chemical epitaxial growth of single crystal CH 3 NH 3 PbBr 3 with controlled locations, morphologies, and orientations, using combined strategies of advanced microfabrication, homoepitaxy, and low temperature solution method is reported. The growth is found to follow a layer-by-layer model. A light emitting diode array, with each CH 3 NH 3 PbBr 3 crystal as a single pixel, with enhanced quantum efficiencies than its polycrystalline counterparts is demonstrated., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oriented composite nanofibers consisting of porous silicon nanoparticles (pSiNPs) embedded in a polycaprolactone or poly(lactide-co-glycolide) matrix are prepared by spray nebulization from chloroform solutions using an airbrush. The nanofibers can be oriented by an appropriate positioning of the airbrush nozzle, and they can direct growth of neurites from rat dorsal root ganglion neurons. When loaded with the model protein lysozyme, the pSiNPs allow the generation of nanofiber scaffolds that carry and deliver the protein under physiologic conditions (phosphate-buffered saline (PBS), at 37 °C) for up to 60 d, retaining 75% of the enzymatic activity over this time period. The mass loading of protein in the pSiNPs is 36%, and in the resulting polymer/pSiNP scaffolds it is 3.6%. The use of pSiNPs that display intrinsic photoluminescence (from the quantum-confined Si nanostructure) allows the polymer/pSiNP composites to be definitively identified and tracked by time-gated photoluminescence imaging. The remarkable ability of the pSiNPs to protect the protein payload from denaturation, both during processing and for the duration of the long-term aqueous release study, establishes a model for the generation of biodegradable nanofiber scaffolds that can load and deliver sensitive biologics., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)