Journal of Nanobiotechnology最新文献

The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood-brain barrier (BBB) often prevents drugs intended for CNS diseases from effectively crossing into the brain parenchyma to deliver their therapeutic effects. The blood-brain barrier is a semi-permeable barrier with high selectivity. The BBB primarily manages the transport of substances between the blood and the CNS. To enhance drug delivery for CNS disease treatment, various brain-based drug delivery strategies overcoming the BBB have been developed. Among them, nanoparticles (NPs) have been emphasized due to their multiple excellent properties. This review starts with an overview of the BBB's anatomical structure and physiological roles, and then explores the mechanisms, both endogenous and exogenous, that facilitate the NP passage across the BBB. The text also delves into how nanoparticles' shape, charge, size, and surface ligands affect their ability to cross the BBB and offers an overview of different nanoparticle classifications. This review concludes with an examination of the current challenges in utilizing nanomaterials for brain drug delivery and discusses corresponding directions for solutions. This review aims to propose innovative diagnostic and therapeutic approaches for CNS diseases and enhance drug design for more effective delivery across the BBB.

Background: Lead-based perovskite nanoparticles (Pb-PNPs) are widely utilized in the photovoltaic industry. However, due to their poor stability and high water solubility, lead often gets released into the environment, which can negatively impact the development of the central nervous system (CNS). As an extension of the CNS, the effects and mechanisms of Pb-PNPs on human retinal development have remained elusive.

Objectives: We aimed to investigate the effects of Pb-PNPs on human retinal development.

Methods: Human embryonic stem cell-derived three-dimensional floating retinal organoids (hEROs) were established to simulate early retinal development. Using immunofluorescence staining, biological-transmission electron microscopy analysis, inductively coupled plasma-mass spectrometry, two-dimensional element distribution detection, and RNA sequencing, we evaluated and compared the toxicity of CsPbBr₃ nanoparticles (a representative substance of Pb-PNPs) and Pb(AC)₂ and investigated the toxicity-reducing effects of SiO₂ encapsulation.

Results: Our findings revealed that CsPbBr₃ nanoparticles exposure resulted in a concentration-dependent decrease in the area and thickness of the neural retina in hEROs. Additionally, CsPbBr₃ nanoparticles exposure hindered cell proliferation and promoted cell apoptosis while suppressing the retinal ganglion cell differentiation, an alteration that further led to the disruption of retinal structure. By contrast, CsPbBr₃ nanoparticles exposure to hEROs was slightly less toxic than Pb(AC)₂. Mechanistically, CsPbBr₃ nanoparticles exposure activated endoplasmic reticulum stress, which promoted apoptosis by up-regulating Caspase-3 and inhibited retinal ganglion cell development by down-regulating Pax6. Interestingly, after coating CsPbBr₃ nanoparticles with silica, it exhibited lower toxicities to hEROs by alleviating endoplasmic reticulum stress.

Conclusion: Overall, our study provides evidence of Pb-PNPs-induced developmental toxicity in the human retina, explores the potential mechanisms of CsPbBr₃ nanoparticles' developmental toxicity, and suggests a feasible strategy to reduce toxicity.

Vascularization as a spatiotemporally interlaced process involving angiogenesis and vascular remodeling, has seldom been investigated comprehensively regarding the interrelationship of the two intertwining but sequential processes. Here, a shortwave infrared (SWIR) fluorescence imaging strategy based on quantum dots (QDs) was designed to dynamically visualize vascularization in vivo and in situ in a perforator transplantation mouse model. The vascularization process could be directly perceived from the established flap model with an optimal observation window at 10 min post-injection. Anchored in SWIR technology and image processing, it was revealed that temporally, angiogenesis lasted throughout 21 days after surgery while vascular remodeling took a dominant role after 14 days both in vivo and in situ. Moreover, four perforasomes of the flap in situ displayed spatially that Zone IV shortened the vascularization process with sufficient blood supply from the LDCIA, while Zone II recovered slowly from ischemia with a lack of blood supply. This study serves as a pioneer in adding novel cognition to spatiotemporal pattern of vascularization through visualizing angiogenesis and vascular remodeling simultaneously and dynamically, thus facilitating further investigation into the mechanisms behind.

This study investigates the application of decellularized tissue matrices (DSCM) hydrogels functionalized with extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) for spinal cord injury (SCI) treatment. The primary focus is on how these composites influence macrophage reprogramming and neural stem cell (NSC) differentiation by modulating Slamf9 expression. MSC-derived EVs were successfully isolated, and DSCM hydrogels were prepared from porcine spinal cords. The composite material, EVs derived from MSCs (DSCM@EVs), was constructed and applied to a mouse SCI model, showing significant enhancement in NSC differentiation and axonal growth, thereby alleviating SCI. Bioinformatics and in vitro cell experiments revealed that DSCM@EVs promote the reprogramming of M1 macrophages to the M2 phenotype, reducing inflammatory responses and facilitating NSC differentiation. RNA-seq analysis identified Slamf9 as a key regulatory gene, with its suppression linked to the observed therapeutic effects. This novel approach demonstrates the potential of DSCM@EVs in SCI repair by modulating the inflammatory environment and promoting neural regeneration, offering a promising strategy for treating SCI and potentially other inflammatory neurological disorders.

The regulation of cardiac cell beating is of great significance for understanding cardiac coordination mechanisms and the treatment of cardiovascular diseases. Inspired by this natural "cell regulates cell" mode in which sinoatrial node cells regulate atrial myocytes, this study presented a novel method to replicate this behavior in vitro through mechanical stimulation. Primary cardiac cells from Sprague-Dawley rats were isolated, cultured in 2D substrates, and applied to precise mechanical stimulation by developing a micro-manipulation platform. We demonstrated that a mechanical probe can act as an external activation device for quiescent cardiac cells, transforming them into "activation cells" capable of activating adjacent "target cells" through bioelectrical coupling. Calcium imaging with Fluo-4 probes revealed that this "cell activates cell" mechanism relies on mechano-electric feedback and calcium-mediated signal propagation via cell junctions. Our findings provide a non-destructive strategy to regulate target cardiac cell, deepen insights into the mechanical modulation of intercellular communication, and offer a framework for studying arrhythmias linked to abnormal cell-cell communication. This work combined mechanical intervention with biological signaling, advancing potential applications in cardiovascular therapeutics.

Long-term exposure to ultraviolet B (UVB) radiation induces the accumulation of free radicals in the skin, resulting in oxidative damage and accelerated aging. As a natural anti-oxidant, squalene has been applied as a cosmetic additive. Nonetheless, the liquid oil state of squalene and its low solubility in water usually limits the practical application of squalene. Recently, phosphotungstate calcium nanowires has been synthesized to gelatinize oily solvents, making it feasible to fabricate stable oleogel formulation containing squalene. Herein, the squalene/phosphotungstate calcium nanowires (Sql/PWC) oleogel has been specifically designed and applied to treat skin photoaging. Such oleogel was comprised of oil-based structures that closely mimic the skin's natural lipids, resulting in enhanced skin penetration, better retention of active ingredients within the skin, and superior stability as compared to traditional hydrogel, especially under UVB exposure. It was found that the application of Sql/PWC oleogel on UVB-irradiated skin successfully decreased epidermal thickness, increased dermal thickness, and promoted the expression of elastin, collagen and skin barrier marker. Meanwhile, RNA-Sequencing results further revealed that the Sql/PWC oleogel alleviated UVB photo-damage through its antioxidant and anti-inflammatory activities in the skin, which were key factors in the aging process. We believe this study will not only bring new perspectives for skin photoaging treatment but also promotes the broader application of oleogel in the cosmetics industry.

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease and current therapies are insufficient to halt its progression. Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) offer promising therapeutic potential for OA treatment, and their efficacy can be enhanced through strategic engineering approaches.

Methods: Inspired by the immune memory of the adaptive immune system, we developed an engineered strategy to impart OA-specific immune memory to MSCs-EVs. Using Luminex technology, inflammatory factors (IFN-γ, IL-6, and TNF-α), which mimic the OA inflammatory microenvironment, were identified and used to prime MSCs, generating immune memory-bearing MSCs-EVs (iEVs). Proteomic analysis and complementary experiments were conducted to evaluate iEVs' effects on macrophage phenotypic reprogramming.

Results: iEVs, particularly IL-6-EV, exhibited potent immunoregulatory functions along with the ability to modulate mitochondrial metabolism. Both in vitro and in vivo, IL-6-EV significantly reprogrammed macrophages towards the M2 subtype, effectively suppressing articular inflammation and OA progression. Mechanistic studies revealed that IL-6-EV facilitated M2 polarization by regulating mitochondrial oxidative phosphorylation via the mt-ND3/NADH-CoQ axis.

Conclusion: This study introduces a strategy to enhance MSCs-EVs' therapeutic efficacy in OA. Multi-omics analysis and biological validation demonstrate its potential, providing new insights for MSCs-EVs' future application in OA and other clinical conditions.

Nanocarrier drug delivery systems (NDDS) have gained momentum in the field of anticancer or nucleic acid drug delivery due to their capacity to aggrandize the targeting efficacy and therapeutic outcomes of encapsulated drugs. A disadvantage of NDDS is that repeated administrations often encounter an obstacle known as the "accelerated blood clearance (ABC) phenomenon". This phenomenon results in the rapid clearance of the secondary dose from the bloodstream and markedly augmented liver accumulation, which substantially undermines the accurate delivery of drugs and the therapeutic effect of NDDS. Nevertheless, the underlying mechanism of this phenomenon has not been elucidated and there is currently no effective method for its eradication. In light of the above, the aim of this review is to provide a comprehensive summary of the underlying mechanism and potential countermeasures of the ABC phenomenon, with a view to rejuvenating both the slow-release property and expectation of NDDS in the clinic. In this paper, we innovatively introduce the pharmacokinetic mechanism of ABC phenomenon to further elucidate its occurrence mechanism after discussing its immunological mechanism, which provides a new direction for expanding the mechanistic study of ABC phenomenon. Whereafter, we conducted a critical conclusion of potential strategies for the suppression or prevention of the ABC phenomenon in terms of the physical and structural properties, PEG-lipid derivatives, dosage regimen and encapsulated substances of nanoformulations, particularly covering some novel high-performance nanomaterials and mixed modification methods. Alternatively, we innovatively propose a promising strategy of applying the characteristics of ABC phenomenon, as the significantly elevated hepatic accumulation and activated CYP3A1 profile associated with the ABC phenomenon are proved to be conducive to enhancing the efficacy of NDDS in the treatment of hepatocellular carcinoma. Collectively, this review is instructive for surmounting or wielding the ABC phenomenon and advancing the clinical applications and translations of NDDS.

The human retina is a fragile and sophisticated light-sensitive tissue in the central nervous system. Unhealthy retinas can cause irreversible visual deterioration and permanent vision loss. Effective therapeutic strategies are restricted to the treatment or reversal of these conditions. In recent years, nanoscience and nanotechnology have revolutionized targeted management of retinal diseases. Pharmaceuticals, theranostics, regenerative medicine, gene therapy, and retinal prostheses are indispensable for retinal interventions and have been significantly advanced by nanomedical innovations. Hence, this review presents novel insights into the use of versatile nanomaterial-based nanocomposites for frontier retinal applications, including non-invasive drug delivery, theranostic contrast agents, therapeutic nanoagents, gene therapy, stem cell-based therapy, retinal optogenetics and retinal prostheses, which have mainly been reported within the last 5 years. Furthermore, recent progress, potential challenges, and future perspectives in this field are highlighted and discussed in detail, which may shed light on future clinical translations and ultimately, benefit patients with retinal disorders.

Triple-negative breast cancer (TNBC) is characterized by high rates of metastasis and recurrence, along with a low sensitivity to immunotherapy, resulting in a paucity of effective therapeutic strategies. Herein, we have developed polydopamine-coated zinc-copper bimetallic nanoplatforms (Cu-ZnO₂@PDA nanoplatforms, abbreviated CZP NPs) that can efficiently induce photothermal amplified cuproptosis and cGAS-STING signaling pathway activation, thereby reversing the immunosuppressive tumor microenvironment of TNBC, upregulating PD-L1 expression, and boosting the efficacy of anti-programmed death-ligand 1 antibody (αPD-L1)-based immunotherapy. Within the acidic tumor microenvironment (TME), CZP NPs spontaneously release copper and zinc ions and hydrogen peroxide, generating highly oxidative hydroxyl radicals and downregulating iron-sulfur cluster proteins. These actions lead to the disruption of mitochondrial integrity, the release of mitochondrial DNA (mtDNA) and irreversible cuproptosis. The further synergy between mtDNA and zinc ions potentiates the activation of the cGAS-STING signaling pathway, triggering a robust antitumor immune response and sensitizing TNBC to αPD-L1 therapy. Additionally, using an 808 nm near-infrared laser for photothermal therapy significantly augments these effects, resulting in a cascade amplification of therapeutic efficacy against TNBC. The strategic combination of CZP NPs with αPD-L1 markedly bolsters antitumor immunity and suppresses tumor growth. Collectively, our findings present a promising synergistic strategy for TNBC treatment by linking cuproptosis, cGAS-STING activation, photothermal therapy, and immunotherapy.