The blood-brain barrier (BBB) is a specialized semipermeable structure that highly regulates exchanges between the central nervous system parenchyma and blood vessels. Thus, the BBB also prevents the passage of various forms of therapeutic agents, nanocarriers, and their cargos. Recently, many multidisciplinary studies focus on developing cargo-loaded nanoparticles (NPs) to overcome these challenges, which are emerging as safe and effective vehicles in neurotheranostics. In this Review, first we introduce the anatomical structure and physiological functions of the BBB. Second, we present the endogenous and exogenous transport mechanisms by which NPs cross the BBB. We report various forms of nanomaterials, carriers, and their cargos, with their detailed BBB uptake and permeability characteristics. Third, we describe the effect of regulating the size, shape, charge, and surface ligands of NPs that affect their BBB permeability, which can be exploited to enhance and promote neurotheranostics. We classify typical functionalized nanomaterials developed for BBB crossing. Fourth, we provide a comprehensive review of the recent progress in developing functional polymeric nanomaterials for applications in multimodal bioimaging, therapeutics, and drug delivery. Finally, we conclude by discussing existing challenges, directions, and future perspectives in employing functionalized nanomaterials for BBB crossing.

Functionalized Nanomaterials Capable of Crossing the Blood-Brain Barrier.

Intracellular zinc ion (Zn2+) accumulation disrupts the Zn2+ homeostasis, providing an ion-overloading anticancer strategy with great potential. The self-adaptation of tumor cells to ion concentration, however, puts forward higher requirements for the design of ion-overloading strategy. Herein, “block and attack” antitumor strategy was applied through a composite nanomaterials (UHSsPZH NPs). The strategy demonstrated powerful ion interference ability through both “blocking” the efflux of excess Zn2+ via gene silencing and “attacking” tumor cells via target delivery of ZnO2. After cellular internalization, ZnO2 was degraded to Zn2+ and hydrogen peroxide (H2O2), and the gene expression of zinc transporter 1 (ZnT1) was silenced by targeting of released siRNA, which together caused intracellular Zn2+-overload. Disorder of Zn2+ further interfered with intracellular Ca2+ homeostasis, inhibited the electron transport chain and promoted the production of endogenous reactive oxygen species (ROS), which assisted the “attack” to tumor cells together with the exogenous ROS generated by UHSsPZH NPs under 980 nm laser irradiation. In summary, this work supplies a “block and attack” strategy for the application of ion homeostasis interference in tumor therapy. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/agt2.321

“Block and attack” strategy for tumor therapy through ZnO
 2
 /siRNA/NIR‐mediating Zn
 2+
 ‐overload and amplified oxidative stress

Engineered bacteria are widely used in cancer treatment because live facultative/obligate anaerobes can selectively proliferate at tumor sites and reach hypoxic regions, thereby causing nutritional competition, enhancing immune responses, and producing anticancer microbial agents in situ to suppress tumor growth. Despite the unique advantages of bacteria-based cancer biotherapy, the insufficient treatment efficiency limits its application in the complete ablation of malignant tumors. The combination of nanomedicine and engineered bacteria has attracted increasing attention owing to their striking synergistic effects in cancer treatment. Engineered bacteria that act as natural vehicles can effectively deliver nanomedicines to tumor sites. Moreover, bacteria provide an opportunity to enhance nanomedicines by modulating the TME and producing substrates to support nanomedicine-mediated anticancer reactions. Nanomedicine exhibits excellent optical, magnetic, acoustic, and catalytic properties, and plays an important role in promoting bacteria-mediated biotherapies. The synergistic anticancer effects of engineered bacteria and nanomedicines in cancer therapy are comprehensively summarized in this review. Attention is paid not only to the fabrication of nanobiohybrid composites, but also to the interpromotion mechanism between engineered bacteria and nanomedicine in cancer therapy. Additionally, recent advances in engineered bacteria-synergized multimodal cancer therapies have also been highlighted. This article is protected by copyright. All rights reserved.

Synergistic Brilliance: Engineered Bacteria and Nanomedicine Unite in Cancer Therapy.

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, affecting hundreds of millions of people globally. Current clinical approaches are confined to providing only symptomatic relief. Research over the past two decades has established that OA is not merely a process of wear and tear of the articular cartilage but involves abnormal remodelling of all joint tissues. Although many new mechanisms of disease have been identified in the past several decades, the efficient and sustainable delivery of drugs targeting these mechanisms in joint tissues remains a major challenge. Nanoparticles recently emerged as favoured delivery vehicles in OA treatment, offering extended drug retention, enhanced drug targeting, and improved drug stability and solubility. In this review, we consider OA as a disease affecting the entire joint and initially explore the pathophysiology of OA across multiple joint tissues, including the articular cartilage, synovium, fat pad, bone, and meniscus. We then classify nanoparticles based on their composition and structure, such as lipids, polymers, inorganic materials, peptides/proteins, and extracellular vesicles. We summarise the recent advances in their use for treatment and diagnosis of OA. Finally, we discuss the current challenges and future directions in this field. In conclusion, nanoparticle-based nanosystems are promising carriers that advance OA treatment and diagnosis. 

Advanced nanoparticles in osteoarthritis treatment.

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future. 

Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System

Engineered nanomaterials (ENMs) with different topographies provide effective nano–bio interfaces for controlling the differentiation of stem cells. The interaction of stem cells with nanoscale topographies and chemical cues in their microenvironment at the nano–bio interface can guide their fate. The use of nanotopographical cues, in particular nanorods, nanopillars, nanogrooves, nanofibers, and nanopits, as well as biochemical forces mediated factors, including growth factors, cytokines, and extracellular matrix proteins, can significantly impact stem cell differentiation. These factors were seen as very effective in determining the proliferation and spreading of stem cells. The specific outgrowth of stem cells can be decided with size variation of topographic nanomaterial along with variation in matrix stiffness and surface structure like a special arrangement. The precision chemistry enabled controlled design, synthesis, and chemical composition of ENMs can regulate stem cell behaviors. The parameters of size such as aspect ratio, diameter, and pore size of nanotopographic structures are the main factors for specific termination of stem cells. Protein corona nanoparticles (NPs) have shown a powerful facet in stem cell therapy, where combining specific proteins could facilitate a certain stem cell differentiation and cellular proliferation. Nano–bio reactions implicate the interaction between biological entities and nanoparticles, which can be used to tailor the stem cells’ culmination. The ion release can also be a parameter to enhance cellular proliferation and to commit the early differentiation of stem cells. Further research is needed to fully understand the mechanisms underlying the interactions between engineered nano–bio interfaces and stem cells and to develop optimized regenerative medicine and tissue engineering designs. 

https://pubs.acs.org/doi/pdf/10.1021/prechem.3c00056

Engineered Nano–Bio Interfaces for Stem Cell Therapy

DNA nanomaterials have been widely employed for various biomedical applications. With rapid development of chemical modification of nucleic acid, serials of stimuli-responsive elements are included in the multifunctional DNA nanomaterials. In this review, we summarize the recent advances in light responsive DNA nanomaterials based on photocleavage/photodecage, photoisomerization, and photocrosslinking for efficient bioimaging (including imaging of small molecule, microRNA, and protein) and drug delivery (including delivery of small molecule, nucleic acid, and gene editing system). We also discuss the remaining challenges and future perspectives of the light responsive DNA nanomaterials in biomedical applications.

Light Responsive DNA Nanomaterials and Their Biomedical Applications.

Nanomaterials‐Mediated Structural and Physiological Modulation of Blood Brain Barrier for Therapeutic Purposes

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Engineered Nano–Bio Interfaces for Stem Cell Therapy

Light Responsive DNA Nanomaterials and Their Biomedical Applications.

Nanomaterials‐Mediated Structural and Physiological Modulation of Blood Brain Barrier for Therapeutic Purposes