Vitality-Enhanced Dual-Modal Tracking System Reveals the Dynamic Fate of Mesenchymal Stem Cells for Stroke Therapy.

Mesenchymal stem cell (MSC) therapy via intravenous transplantation exhibits great potential for brain tissue regeneration, but still faces thorny clinical translation challenges as the unknown dynamic fate leads to the contentious therapeutic mechanism and the poor MSC viability in harsh lesions limits therapeutic efficiency. Here, a vitality-enhanced dual-modal tracking system is designed to improve engraftment efficiency and is utilized to noninvasively explore the fate of intravenous transplanted human umbilical cord-derived MSCs during long-term treatment of ischemic stroke. Such a system is obtained by bioorthogonally conjugating magnetic resonance imaging (MRI) contrast and near-infrared fluorescence (NIRF) imaging nanoparticles to metabolic glycoengineered MSCs with a lipoic acid-containing extracellular antioxidative protective layer. The dynamic fates of MSCs in multi-dimensional space-time evolution are digitally detailed for up to 28 days using MRI and NIRF imaging equipment, and the protective layer greatly shields MSCs from reactive oxygen spices (ROS) degradation, enhances MSC survival, and engraftment efficiency. Additionally, it is observed that the bioengineered MSCs exhibit dynamic intelligent responses corresponding to microenvironment remodeling and exert enhanced therapeutic effects. This dual-modal tracking system enables long-term tracking of MSCs while improving their viability at the lesion sites, which may serve as a valuable tool for expediting the clinical translation of MSC therapy.

Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)phenyl-2,4-dinitrobenzenesulfonate and Fe3+ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.

Metformin and Docosahexaenoic Acid Hybrid Micelles for Premetastatic Niche Modulation and Tumor Metastasis Suppression.

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.

Sequential Targeting TGF-ß Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-ß) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-ß and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-ß signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.

Biomimetic ApoE-Reconstituted High Density Lipoprotein Nanocarrier for Blood-Brain Barrier Penetration and Amyloid Beta-Targeting Drug Delivery.

Amyloid beta (Aß) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers that possess both blood-brain barrier permeability and Aß-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aß oligomers and fibrils and accelerate Aß cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aß aggregates. Following the loading of α-M, the Aß-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aß1-42 was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.

High-density lipoprotein-biomimetic nanocarriers for glioblastoma-targeting delivery: the effect of shape.

Rational design of the physicochemical properties of nanocarriers can optimize their pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. In particular, particle shape is one of the crucial parameters that can impact the circulation time, tumor accumulation and tumor cell internalization of nanocarrier. Biomimetic reconstituted high-density lipoprotein (rHDL), by mimicking the endogenous shape and structure of high-density lipoprotein, has been indicated as a promising tumor-targeting nanoparticulate drug delivery system whereas the effect of shape on tumor-targeting efficiency has not been fully evaluated. Herein, we constructed apolipoprotein E-based biomimetic rHDL in both discoidal form (d-rHDL) and spherical form (s-rHDL), and compared their efficiency in glioblastoma multiforme (GBM)-targeting delivery. s-rHDL showed higher cellular association in GBM cells especially at a high exposure dosage or after a long incubation time. Moreover, it exhibited deeper penetration in 3D GBM spheroids in vitro and higher accumulation at the GBM site in vivo with the GBM-targeting accumulation of s-rHDL increased by 73% when compared with that of d-rHDL at 24 h post-injection. The findings collectively indicated that s-rHDL might serve as a more efficient nanocarrier for glioblastoma-targeting drug delivery.

Mammary-Derived Growth Inhibitor Targeting Peptide-Modified PEG-PLA Nanoparticles for Enhanced Targeted Glioblastoma Therapy.

Targeting delivery of chemotherapeutics to neovasculature represents a promising means for tumor therapy since angiogenesis has been a featured hallmark of glioblastma. However, anti-angiogenic therapy would induce the occurrence of metastatic tumor and even neoplasm recurrence. Simultaneous targeting of tumor cells and neovasculature perfectly overcome such defects and has been proven to be an efficacious strategy for suppressing tumor growth. In the present study, a tumor homing peptide CooP selective binding to mammary-derived growth inhibitor that overexpressed in glioma cells and blood vessel endothelial cells was decorated on the surface of paclitaxel-loading PEG-PLA nanoparticles (NP-PTX) to obtain the dual targeting nanovector CooP-NP-PTX. In vitro antiproliferation study showed that HUVEC cells and U87MG cells were much more sensitive to CooP-NP-PTX than NP-PTX. In vivo imaging demonstrated that CooP-NP accumulated more selectively and penetrated deeper into the tumor site. In addition, the glioma-bearing mice treated with CooP-NP-PTX achieved the longest survival time compared to NP-PTX and Taxol. The findings observed above indicated that CooP peptide-functionalized anti-neoplastic agent-loaded nanoparticles might possess promising potential for glioblastoma therapy.

Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex.

Treatment of glioblastoma (GBM) remains to be the most formidable challenge because of the hindrance of the blood-brain barrier (BBB) along with the poor drug penetration into the glioma parenchyma. Nanoparticulate drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting ligand to target the glioma-associated transferrin receptor (TfR) had met the problem of loss of specificity in biological environment due to the high level of endogenous Tf. Here we conjugated CRT peptide, an iron-mimicry moiety targeting the whole complex of Tf/TfR, to poly(ethylene glycol)-poly(l-lactic-co-glycolic acid) nanoparticles (CRT-NP), to open a new route to overcome such obstacle. High cellular associations, advanced transport ability through the BBB model, and penetration in 3-dimensional C6 glioma spheroids in vitro had preliminarily proved the advantages of CRT-NP over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP, and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior antiproliferation effect on C6 glioma cells and stronger inhibitory effect on glioma spheroids. Favored pharmacokinetics behavior and enhanced accumulation in glioma foci was observed, together with a much deeper distribution pattern in glioma parenchyma compared with unmodified nanoparticles and Tf-NP. Eventually, mice treated with CRT-NP-PTX showed a remarkably prolonged median survival compared to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification of CRT to nanoparticles holds great promise for enhancement of antiglioma therapy.

Co-administration of dual-targeting nanoparticles with penetration enhancement peptide for antiglioblastoma therapy.

Chemotherapy is an indispensable auxiliary treatment for glioma but highly limited by the existence of both blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). The dysfunctional brain tumor blood vessels and high interstitial pressure in glioma also greatly hindered the accumulation and deep penetration of chemotherapeutics into the glioma. Lactoferrin (Lf), with its receptor overexpressed on both the brain endothelial cells and glioma cells, was here functionalized to the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to mediate BBB/BBTB and glioma cell dual targeting. tLyP-1, a tumor-homing peptide, which contains a C-end Rule sequence that can mediate tissue penetration through the neuropilin-1-dependent internalization pathway, was coadministrated with Lf-functionalized nanoparticles (Lf-NP) to enhance its accumulation and deep penetration into the glioma parenchyma. Enhanced cellular association in both BCEC and C6 cells, increased cytotoxicity of the loaded paclitaxel, and deep penetration in the 3D glioma spheroids was achieved by Lf-NP. Following coadministration with tLyP-1, the functionalized nanoparticles obtained improved tumor targeting, glioma vascular extravasation, and antiglioma efficacy. The findings here suggested that the strategy by coadministrating BBB/BBTB and glioma cells dual-targeting nanocarriers with a tumor penetration enhancement peptide represent a promising platform for antiglioma drug delivery.

Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway.

Intranasal delivery provides a direct and non-invasive method for drugs to reach the central nervous system. Nanoparticles play a crucial role as carriers in augmenting the efficacy of brain delivery. However, the interaction between nanoparticles and the nose-to-brain pathway and how the various biopharmaceutical factors affect brain delivery efficacy remains unclear. In this review, we comprehensively summarized the anatomical and physiological characteristics of the nose-to-brain pathway and the obstacles that hinder brain delivery. We then outlined the interaction between nanoparticles and this pathway and reviewed the biomedical applications of various nanoparticulate drug delivery systems for nose-to-brain drug delivery. This review aims at inspiring innovative approaches for enhancing the effectiveness of nose-to-brain drug delivery in the treatment of different brain disorders.

Intracerebral fate of organic and inorganic nanoparticles is dependent on microglial extracellular vesicle function.

Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood-brain barrier. However, NP clearance is critical for safety and therapeutic applicability. Here we report on a study of the clearance of model organic and inorganic NPs from the brain. We find that microglial extracellular vesicles (EVs) play a crucial role in the clearance of inorganic and organic NPs from the brain. Inorganic NPs, unlike organic NPs, perturb the biogenesis of microglial EVs through the inhibition of ERK1/2 signalling. This increases the accumulation of inorganic NPs in microglia, hindering their elimination via the paravascular route. We also demonstrate that stimulating the release of microglial EVs by an ERK1/2 activator increased the paravascular glymphatic pathway-mediated brain clearance of inorganic NPs. These findings highlight the modulatory role of microglial EVs on the distinct patterns of the clearance of organic and inorganic NPs from the brain and provide a strategy for modulating the intracerebral fate of NPs.

Comparative Proteomics Inspired Self-Stimulated Release Hydrogel Reinforces the Therapeutic Effects of MSC-EVs on Alzheimer's Disease.

The clinical application of extracellular vesicles (EVs)-based therapeutics continues to be challenging due to their rapid clearance, restricted retention, and low yields. Although hydrogel possesses the ability to impede physiological clearance and increase regional retention, it typically fails to effectively release the incorporated EVs, resulting in reduced accessibility and bioavailability. Here an intelligent hydrogel in which the release of EVs is regulated by the proteins on the EVs membrane is proposed. By utilizing the EVs membrane enzyme to facilitate hydrogel degradation, sustained retention and self-stimulated EVs release can be achieved at the administration site. To achieve this goal, the membrane proteins with matrix degrading activity in the mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are identified using comparative proteomics. After that, a hydrogel comprised of self-assembled peptides that are susceptible to degradation by the membrane enzymes present in MSC-EVs is designed and synthesized. After intranasal administration, this peptide hydrogel facilitates sustained and thermo-sensitive release of MSC-EVs, thereby extending the retention of the MSC-EVs and substantially enhancing their potential for treating Alzheimer's disease. This research presents a comparative proteomics-driven approach to intelligent hydrogel design, which holds the capacity to significantly enhance the applicability of EVs in clinical settings.

Self-Disassembling and Oxygen-Generating Porphyrin-Lipoprotein Nanoparticle for Targeted Glioblastoma Resection and Enhanced Photodynamic Therapy.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO2) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

Biologically Self-Assembled Tumor Cell-Derived Cancer Nanovaccines as an All-in-One Platform for Cancer Immunotherapy.

Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.

Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis.

Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.

Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.

Activatable cell penetrating peptide-conjugated nanoparticles with enhanced permeability for site-specific targeting delivery of anticancer drug.

Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the overexpression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy.

B6 peptide-modified PEG-PLA nanoparticles for enhanced brain delivery of neuroprotective peptide.

The blood-brain barrier (BBB), which is formed by the brain capillary wall, greatly hinders the development of new drugs for the brain. Over the past decades, among the various receptor-mediated endogenous BBB transport systems, the strategy of using transferrin or anti-transferrin receptor antibodies to facilitate brain drug delivery system is of particular interest. However, the application of large proteins still suffers from the drawbacks including synthesis procedure, stability, and immunological response. Here, we explored a B6 peptide discovered by phase display as a substitute for transferrin, and conjugated it to PEG-PLA nanoparticles (NP) with the aim of enhancing the delivery of neuroprotective drug across the BBB for the treatment of Alzheimer's disease. B6-modified NP (B6-NP) exhibited significantly higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. In vivo, fluorescently labeled B6-NP exhibited much higher brain accumulation when compared with NP. Administration of B6-NP encapsulated neuroprotective peptide-NAPVSIPQ (NAP)-to Alzheimer's disease mouse models showed excellent amelioration in learning impairments, cholinergic disruption, and loss of hippocampal neurons even at lower dose. These findings together suggested that B6-NP might serve as a promising DDS for facilitating the brain delivery of neuropeptides.

Orientational fluctuations near the smectic A to smectic C phase transition in two "de Vries"-type liquid crystals.

On the basis of thorough analysis of 2D X-ray diffraction patterns from smectic monodomains, we examine the influence of orientational fluctuations on the weakly first-order smectic A (SmA) to smectic C (SmC) transitions in two nonchiral organosiloxane "de Vries"-type liquid crystals. We find that these materials exhibit very large molecular tilt fluctuations with magnitudes of up to 35°--thus larger than the average tilt itself. This is essential to understand the underlying molecular mechanism behind the practical absence of smectic layer contraction in these materials: in the SmA phase, the nematic order parameter is very low (molecular fluctuations correspondingly high), and the expected layer shrinkage at the SmA to SmC transition is almost fully compensated by the increase in orientational order, as the fluctuations diminish with decreasing temperature. In addition to the general tilt fluctuations, we observe intrinsic soft-mode fluctuations. They have a λ-shaped temperature dependence that peaks at the SmA-SmC transition with a maximum amplitude of about 2°.

Nano-Brake Halts Mitochondrial Dysfunction Cascade to Alleviate Neuropathology and Rescue Alzheimer's Cognitive Deficits.

Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). The dysregulation of mitochondrial calcium ion (Ca2+ ) homeostasis and the mitochondrial permeability transition pore (mPTP), is a critical upstream signaling pathway that contributes to the mitochondrial dysfunction cascade in AD pathogenesis. Herein, a "two-hit braking" therapeutic strategy to synergistically halt mitochondrial Ca2+ overload and mPTP opening to put the mitochondrial dysfunction cascade on a brake is proposed. To achieve this goal, magnesium ion (Mg2+ ), a natural Ca2+ antagonist, and siRNA to the central mPTP regulator cyclophilin D (CypD), are co-encapsulated into the designed nano-brake; A matrix metalloproteinase 9 (MMP9) activatable cell-penetrating peptide (MAP) is anchored on the surface of nano-brake to overcome the blood-brain barrier (BBB) and realize targeted delivery to the mitochondrial dysfunction cells of the brain. Nano-brake treatment efficiently halts the mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, and microglia and powerfully alleviates AD neuropathology and rescues cognitive deficits. These findings collectively demonstrate the potential of advanced design of nanotherapeutics to halt the key upstream signaling pathways of mitochondrial dysfunction to provide a powerful strategy for AD modifying therapy.