Design Of Nanomedicines Research Articles

Unearth the ultrapotent intrinsic fungicidal efficacy of the surface-piercing CuFeSe2-PVP nano-blade

The critical shortage of antifungal drugs and increasingly emerged resistant fungi urgently call for the development of novel fungicidal agents with translational potential. Although nanodrugs compose a new antifungal arsenal, the fungicidal efficacy barely exceeds clinical molecules. In this study, a CuFeSe2-PVP nano-blade, is unexpectedly discovered with ultrapotent intrinsic fungicidal efficacy. This nanostructure is facilely fabricated by a specific aqueous precipitation method with the nucleation of tetragonal eskebornite CuFeSe2 at PVP chains. The unique semiconductor CuFeSe2-PVP demonstrates superior antifungal activity than the commonly used small-molecule drugs and metal nanoparticles in both planktonic fungi and biofilm. Intriguingly, electron microscopy visualizes that the nano-blades cut fungal membranes with fungi surfaces inserted by the blades. Such a membrane-piercing effect results in the loss of important intracellular components, including nucleic acids, proteins, and potassium ions. Increased intracellular reactive oxygen species (ROS) is also observed. Encouragingly, in mice with subcutaneous fungal infection, the nanodrug achieves absolute fungi clearance, effectively alleviating inflammation and promoting collagen fiber recovery. Moreover, the excellent biocompatibility of CuFeSe2-PVP promises great potential for further translation. This study not only provides a novel fungicidal drug candidate, but also inspires the future design of anti-fungal nanomedicine.

Nanoparticles that Transcytosed through Cancer Cells Can Elicit Immune Response.

Transcytosis is a crucial process that nanomedicines can experience in various delivery stages. However, little was known about whether it endows biofunctions to the nanomedicines. Here, we reported that transporting photodynamic nanoparticles across cancer cells via the endoplasmic reticulum (ER)-Golgi pathway formulated them with abundant neoantigens and damage-associated molecular patterns. The resultant nanoparticles (Tran-NPs) were potent in dendritic cell maturation and T cell activation. Meanwhile, the photodynamic Tran-NPs maintained their primary function of repolarizing immunosuppressive cells. The immune responses were observed in melanoma B16F10 tumor models. Our work suggested that the transcytosis process reprogrammed the nanoparticles with immunological properties, which might shed light on the design of nanomedicines.

BPA‐Containing Polydopamine Nanoparticles for Boron Neutron Capture Therapy in a U87 Glioma Orthotopic Model

AbstractBoron neutron capture therapy (BNCT) is a promising therapy for refractory cancer based on the cytotoxic reaction of 10B (n, α) 7Li. Although two BNCT agents are clinically available, they are quickly metabolized and show modest enrichment in tumor sites, partially limiting BNCT widespread application. Consequently, novel agents that perform active targeting and show good biocompatibility have to be developed. Herein, boronophenylalanine‐containing polydopamine (B‐PDA) nanoparticles are easily fabricated by encapsulating boronophenylalanine (BPA) in polydopamine via nitrogen‐boronate coordination. In this study, B‐PDA achieves increased tumor accumulation and prolonged retention effects in the tumor site and superior antitumor activity post neutron irradiation in the orthotopic xenograft glioma model. In brief, this study offers a novel strategy for BPA delivery and may broaden the perspective on nanomedicine design for BNCT.

Design of a new self-assembling antioxidant nanomedicine to ameliorate oxidative stress in zebrafish embryos.

Oxidative stress, which is a persistent state of elevated reactive oxygen species (ROS), is implicated in the pathogeneses of several diseases, making antioxidant-based therapeutics the aptest intervention. Nevertheless, the clinical failure of conventional low-molecular-weight (LMW) antioxidants in oxidative stress-related diseases to yield favorable therapeutic outcomes and an increased mortality rate attributable to their poor pharmacokinetic characteristics, necessitates the development of alternative therapeutics. In light of this, we designed and synthesized a new amphiphilic polymer functionalized with a clinically safe base polymer of poly(styrene-co-maleic anhydride) copolymer conjugated with the LMW pleiotropic antioxidant TEMPO (a potent antioxidant) and biocompatible poly(ethylene glycol) (TEMPO-installed PSMA-g-PEG), which self-assembles into nano-sized micelles (SMAPoTN) under physiological conditions. We investigated its safety and antioxidant ability using zebrafish models. Common LMW antioxidants, such as 4-hydroxy-TEMPO (TEMPOL), vitamin C, N-acetyl-L-cysteine, and edaravone exposure induced phenotypic distortions, a manifestation of developmental toxicity, and resulted in high lethality in zebrafish larvae. LMW TEMPOL also adversely affected embryo hatchability, induced arrhythmia and cardiac edema, and failed to protect against oxidative stress. In contrast, exposure of zebrafish embryos to SMAPoTN increased the hatchability, protected embryos against various inducers of oxidative stress, and did not induce any phenotypic alterations or discernible toxicity. Taken together, we conclude that SMAPoTN surpasses LMW TEMPOL in terms of the ability to protect zebrafish, attributable to efficient ROS scavenging without perturbing normal redox homeostasis. These results imply that SMAPoTN can be used as a therapeutic intervention against various oxidative stress-induced diseases. STATEMENT OF SIGNIFICANCE: Failure of low molecular weight (LMW) antioxidants to improve therapeutic index in various oxidative stress-related pathogenesis, attributable to their poor pharmacokinetic characteristics, greatly limits their clinical translation. To overcome this limitation, we developed a self-assembling antioxidant nanoparticle (SMAPoTN) comprised of amphiphilic polymer; poly(styrene-co-maleic anhydride) conjugated with TEMPO as an antioxidant and biocompatible poly(ethylene glycol). Preliminary studies carried out in the in vivo models of zebrafish embryos confirmed that exposure of LMW antioxidant resulted in acute developmental toxicity, high lethality, and failure to rescue embryos against oxidative stress inducers. In contrast, SMAPoTN did not exert discernible toxicity and significantly improved their survival under oxidative stress. Our finding establishes antioxidant nanoparticles as more suitable therapeutic intervention for oxidative stress-induced diseases than LMW antioxidants.

An experimental and theoretical approach to understand the interaction between particles and mucosal tissues.

Nanonization of poorly water-soluble drugs has shown great potential in improving their oral bioavailability by increasing drug dissolution rate and adhesion to the gastrointestinal mucus. However, the fundamental features that govern the particle-mucus interactions have not been investigated in a systematic way before. In this work, we synthesize mucin hydrogels that mimic those of freshly excised porcine mucin. By using fluorescent pure curcumin particles, we characterize the effect of particle size (200 nm, and 1.2 and 1.3 μm), concentration (18, 35, and 71 μg mL-1), and hydrogel crosslinking density on the diffusion-driven particle penetration in vitro. Next, we derive a phenomenological model that describes the physics behind the diffusion-derived penetration and considers the contributions of the key parameters assessed in vitro. Finally, we challenge our model by assessing the oral pharmacokinetics of an anti-cancer model drug, namely dasatinib, in pristine and nanonized forms and two clinically relevant doses in rats. For a dose of 10 mg kg-1, drug nanonization leads to a significant ∼8- and ∼21-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the unprocessed drug. When the dose of the nanoparticles was increased to 15 mg kg-1, the oral bioavailability increased though not significantly, suggesting the saturation of the mucus penetration sites, as demonstrated by the in vitro model. Our overall results reveal the potential of this approach to pave the way for the development of tools that enable a more rational design of nano-drug delivery systems for mucosal administration. STATEMENT OF SIGNIFICANCE: The development of experimental-theoretical tools to understand and predict the diffusion-driven penetration of particles into mucus is crucial not only to rationalize the design of nanomedicines for mucosal administration but also to anticipate the risks of the exposure of the body to nano-pollutants. However, a systematic study of such tools is still lacking. Here we introduce an experimental-theoretical approach to predict the diffusion-driven penetration of particles into mucus and investigate the effect of three key parameters on this interaction. Then, we challenge the model in a preliminary oral pharmacokinetics study in rats which shows a very good correlation with in vitro results. Overall, this work represents a robust platform for the modelling of the interaction of particles with mucosae under dynamic conditions.

An Engineered Design of Self-Assembly Nanomedicine Guided by Molecular Dynamic Simulation for Photodynamic and Hypoxia-Directed Therapy.

To overcome the hypoxia barrier in tumor therapy, a hypoxia-activated prodrug of docetaxel (DTX-PNB) was synthesized and self-assembled with indocyanine green (ICG), forming a combination nanomedicine ISDNN. With the guidance of molecular dynamic simulation, the ISDNN construction could be accurately controlled, achieving uniform size distribution and high drug loading up to 90%. Within the hypoxic tumor environment, ISDNN exerted ICG-mediated photodynamic therapy and aggravated hypoxia to boost DTX-PNB activation for chemotherapy, enabling enhanced antitumor efficacy.

Peptide Self-Assembled Nanocarriers for Cancer Drug Delivery.

The design of novel cancer drug nanocarriers is critical in the framework of cancer therapeutics. Nanomaterials are gaining increased interest as cancer drug delivery systems. Self-assembling peptides constitute an emerging novel class of highly attractive nanomaterials with highly promising applications in drug delivery, as they can be used to facilitate drug release and/or stability while reducing side effects. Here, we provide a perspective on peptide self-assembled nanocarriers for cancer drug delivery and highlight the aspects of metal coordination, structure stabilization, and cyclization, as well as minimalism. We review particular challenges in nanomedicine design criteria and, finally, provide future perspectives on addressing a portion of the challenges via self-assembling peptide systems. We consider that the intrinsic advantages of such systems, along with the increasing progress in computational and experimental approaches for their study and design, could possibly lead to novel classes of single or multicomponent systems incorporating such materials for cancer drug delivery.

Machine-learning-assisted single-vessel analysis of nanoparticle permeability in tumour vasculatures.

The central dogma that nanoparticle delivery to tumours requires enhanced leakiness of vasculatures is a topic of debate. To address this, we propose a single-vessel quantitative analysis method by taking advantage of protein-based nanoprobes and image-segmentation-based machine learning (nano-ISML). Using nano-ISML, >67,000 individual blood vessels from 32 tumour models were quantified, revealing highly heterogenous vascular permeability of protein-based nanoparticles. There was a >13-fold difference in the percentage of high-permeability vessels in different tumours and >100-fold penetration ability in vessels with the highest permeability compared with vessels with the lowest permeability. Our data suggest passive extravasation and transendothelial transport were the dominant mechanisms for high- and low-permeability tumour vessels, respectively. To exemplify the nano-ISML-assisted rational design of nanomedicines, genetically tailored protein nanoparticles with improved transendothelial transport in low-permeability tumours were developed. Our study delineates the heterogeneity of tumour vascular permeability and defines a direction for the rational design of next-generation anticancer nanomedicines.

Polymeric Metal Contrast Agents for T1-Weighted Magnetic Resonance Imaging of the Brain.

Imaging plays an integral role in diagnostics and treatment monitoring for conditions affecting the brain; enhanced brain imaging capabilities will improve upon both while increasing the general understanding of how the brain works. T1-weighted magnetic resonance imaging is the preferred modality for brain imaging. Commercially available contrast agents, which are often required to render readable brain images, have considerable toxicity concerns. In recent years, much progress has been made in developing new contrast agents based on the magnetic features of gadolinium, iron, or magnesium. Nanotechnological approaches for these systems allow for the protected integration of potentially harmful metals with added benefits like reduced dosage and improved transport. Polymeric enhancement of each design further improves biocompatibility while allowing for specific brain targeting. This review outlines research on polymeric nanomedicine designs for T1-weighted contrast agents that have been evaluated for performance in the brain.

Amplifying STING activation by bioinspired nanomedicine for targeted chemo- and immunotherapy of acute myeloid leukemia.

Chemotherapy resistance and the tumor immune microenvironment are dual reasons for the poor therapeutic efficacy of treating acute myeloid leukemia (AML), causing suboptimal clinical outcomes and high relapse rates. Activation of the stimulator of interferon genes (STING) pathway based on innate immunity can effectively improve antitumor immunity. However, traditional STING agonists are limited due to their easy degradation and difficult membrane transport. Here, a bioinspired nanomedicine synergizing chemo- and immunotherapy was developed by activating the STING pathway for targeted and systemic AML cell damage. We show that a leukemia cell membrane (LCM)-camouflaged hollow MnO2 nanocarrier (HM) with encapsulated doxorubicin (DOX) (denoted LHMD) could bind specifically to AML cells with a homologous targeting effect. Then, MnO2 was decomposed into Mn2+ in response to endosomal acid and glutathione (GSH), which improved the magnetic resonance imaging (MRI) signal for AML detection and activated the STING pathway. In mouse models, LHMD was confirmed to eradicate established AML and prevent the engraftment of AML cells. The percentages of T-helper 1 (Th1) and T-helper 17 (Th17) cells and the concentrations of type I interferon (IFN-Ⅰ) and proinflammatory cytokines increased, while the percentage of T-helper 2 (Th2) cells decreased, reflecting the anti-AML immune response induced by Mn2+ after treatment with LHMD. This nanotechnology-based therapeutic regimen may represent a generalizable strategy for generating an anti-leukemia immune response. STATEMENT OF SIGNIFICANCE: Relapse and chemotherapy refractoriness are main causes for the dismal prognosis of AML, making it urgent to develop more effective anti-AML therapies. This study proposes an innovative strategy to combat this issue by designing a biomimetic BM-targeted nanomedicine based on a MnO2 nano-carrier to rationally deliver chemotherapeutic agents and to trigger Mn2+ mediated STING pathway activation for potent immune- and chemotherapy against AML cells. Hence, the nanomedicine design addresses the challenges associated with AML therapy and proposes a promising strategy to improve the therapeutic efficacy against AML.

Aminopeptidase N-Responsive Conjugates with Tunable Charge-Reversal Properties for Highly Efficient Tumor Accumulation and Penetration.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment.

Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.

DNA Nanomaterials-Based Platforms for Cancer Immunotherapy.

The past few decades have witnessed the evolving paradigm for cancer therapy from nonspecific cytotoxic agents to selective, mechanism-based therapeutics, especially immunotherapy. In particular, the integration of nanomaterials with immunotherapy is proven to improve the therapeutic outcome and minimize off-target toxicity in the treatment. As a novel nanomaterial, DNA-based self-assemblies featuring uniform geometries, feasible modifications, programmability, surface addressability, versatility, and intrinsic biocompatibility, are extensively exploited for innovative and effective cancer immunotherapy. In this review, the successful employment of DNA nanoplatforms for cancer immunotherapy, including the delivery of immunogenic cell death inducers, adjuvants and vaccines, immune checkpoint blockers as well as the application in immune cell engineering and adoptive cell therapy is summarized. The remaining challenges and future perspectives regarding the pharmacokinetics/pharmacodynamics, in vivo fate and immunogenicity of DNA materials, and the design of intelligent DNA nanomedicine for individualized cancer immunotherapy are also discussed.

Mitochondrial-targeting Mn3O4/UIO-TPP nanozyme scavenge ROS to restore mitochondrial function for osteoarthritis therapy.

Excessive reactive oxygen species (ROS)-induced mitochondrial damage has impact on osteoarthritis (OA). Nanozyme mimics as natural enzyme alternatives to scavenge excessive ROS has offered a promising strategy for OA therapy. Herein, we reported a novel mitochondrial-targeting Mn3O4/UIO-TPP nanozyme using metal-organic frameworks with loaded Mn3O4 as the enzyme-like active core combining mitochondria-targeting triphenylphosphine (TPP) groups to serve as ROS scavengers for therapy of OA. With sequential catalysis of superoxide dismutase-like, catalase (CAT)-like, and hydroxyl radical (·OH) scavenging potentials, the nanozyme can target mitochondria by crossing subcellular barriers to effectively eliminate ROS to restore mitochondrial function and inhibit inflammation and chondrocyte apoptosis. It also has favorable biocompatibility and biosafety. Based on anterior cruciate ligament transection-induced OA joint models, this mitochondrial-targeting nanozyme effectively mitigated the inflammatory response with the Pelletier score reduction of 49.9% after 8-week therapy. This study offers a prospective approach to the design of nanomedicines for ROS-related diseases.

Predicting efficacy of drug-carrier nanoparticle designs for cancer treatment: a machine learning-based solution

Molecular Dynamic (MD) simulations are very effective in the discovery of nanomedicines for treating cancer, but these are computationally expensive and time-consuming. Existing studies integrating machine learning (ML) into MD simulation to enhance the process and enable efficient analysis cannot provide direct insights without the complete simulation. In this study, we present an ML-based approach for predicting the solvent accessible surface area (SASA) of a nanoparticle (NP), denoting its efficacy, from a fraction of the MD simulations data. The proposed framework uses a time series model for simulating the MD, resulting in an intermediate state, and a second model to calculate the SASA in that state. Empirically, the solution can predict the SASA value 260 timesteps ahead 7.5 times faster with a very low average error of 1956.93. We also introduce the use of an explainability technique to validate the predictions. This work can reduce the computational expense of both processing and data size greatly while providing reliable solutions for the nanomedicine design process.

Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy.

Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.

Commentary: Nanoparticle-Based Chemotherapy Delivery and Potential Health Risks: Prospects for Effective Clinical Translation.

With recent advancements, chemotherapy is one of the most prevalent regimens for cancer treatment. However, the heterogeneity of tumor biology and healthy cell-damaging potential of chemotherapy remain challenges. As a solution, nanoparticle-based delivery is advancing. Besides its promising potential, effective clinical translation and commercialization of nanoparticle-based chemotherapy should get attention to ensure the absence of potential health risks. Specifically, the permeability potential of nanoparticles across biological barriers can lead to drug accumulation in vital organs and produce harm. Therefore, for effective design and clinical application of next-generation nanomedicine, pharmaceutical formulation scientists should conduct intensive studies. They involve studying the properties of drug-loaded nanoparticles in the microenvironment of the target site and the impact of interspecies differences using quantitative and mechanistic studies. It creates a comprehensive understanding of the specific properties of nanoparticles and their interaction potential with biological systems. This commentary justifies the requirement for comprehensive knowledge of the above-mentioned criteria and tests for the success of nanomedicine for chemotherapy delivery.

Reaching new lights: a review on photo-controlled nanomedicines and their in vivo evaluation.

The selective and efficient delivery of bioactive molecules to sites of interest remains a formidable challenge in medicine. In recent years, it has been shown that stimuli-responsive drug delivery systems display several advantages over traditional drug administration such as an improved pharmacokinetic profile and the desirable ability to gain control over release. Light emerged as one of the most powerful stimuli due to its high biocompatibility, spatio-temporal control, and non-invasiveness. On the road to clinical translation, various chemical systems of high complexity have been reported with the aim to improve efficacy, safety, and versatility of drug delivery under complex biological conditions. For future research on the chemical design of such photo-controlled nanomedicines, it is essential to gain an understanding of their in vivo translation and efficiency. Here, we discuss photo-controlled nanomedicines that have been evaluated in vivo and provide an overview of the state-of-the-art that should guide future research design.

Photo-activated autophagy-associated tumour cell death by lysosome impairment based on manganese-doped graphene quantum dots.

Autophagy is indispensable in normal cellular processes, yet detrimental to cancer treatment because it severely lowers the therapeutic efficiency. One of the keys to solve this problem may lie in lysosomes, which requires the rational design of nanomedicine that is capable of localizing and maintaining its efficacy in lysosomes. In this work, a facile and versatile nanoplatform based on manganese-doped graphene quantum dots (Mn-FGQDs) is developed for effective and precise photodynamic impairment of lysosomes. Specifically, the incorporation of Mn not only strengthens the generation capability of reactive oxygen species (ROS), but also facilitates its accumulation in lysosomes. Moreover, Mn-FGQDs are structurally robust and retain their high photodynamic efficiency in the lysosomal environment. On this basis, the light-triggered generation of ROS would primarily influence the function of lysosomes, leading to lysosome impairment and thereby effectively blocking the protective autophagy recycling. More impressively, a continuous increase in the oxidative stress level in lysosomes causes severe autophagy dysfunction, as revealed from an abnormal increase in autophagosomes and autolysosomes. This eventually results in autophagy-associated cancer cell death accompanied by the characteristics of apoptosis and ferroptosis. Overall, the present work paves a new way for cancer therapy via precise lysosome impairment induced autophagy dysfunction.

A transdermal drug delivery system based on dissolving microneedles for boron neutron capture therapy of melanoma.

Boron neutron capture therapy (BNCT) is a promising therapy for malignant tumors that requires selective and high concentrations of 10B accumulation in tumor cells. Despite ongoing developments in novel boron agents and delivery carriers, the progress and clinical application of BNCT is still restricted by the low 10B accumulation and tumor-to-normal tissue (T/N) ratio. Herein, a dissolving microneedle-based transdermal drug delivery system was specifically designed for BNCT in a mouse model of melanoma. By incorporating fructose-BPA (F-BPA) into PVA microneedle tips, this system successfully delivered sufficient F-BPA into the melanoma site after the application of only two patches. Notably, the T/N ratio achieved through the treatment combining PVA/F-BPA MNs with BNCT (PVA/F-BPA MNs-BNCT) surpassed 93.16, signifying a great improvement. Furthermore, this treatment approach effectively inhibited tumor growth and significantly enhanced the survival rate of the mice. In brief, our study introduces a novel, simple, and efficient administration strategy for BNCT, opening new possibilities for the design of nanomedicine for BNCT.