Multifunctional Nanomedicine Research Articles

Platelet Membrane-Camouflaged Copper Doped CaO2 Biomimetic Nanomedicines for Breast Cancer Combination Treatment.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide. Chemodynamic therapy (CDT), photothermal therapy (PTT), and ion interference therapy (IIT), used in combination, represent a common treatment. In this study, platelet membrane-camouflaged copper-doped CaO2 biomimetic nanomedicines have been developed for breast cancer treatments. Copper-doped CaO2 nanoparticles were first coated by polydopamine (PDA) and subsequently camouflaged by platelet membrane (PM) to form platelet membrane-camouflaged copper doped CaO2 biomimetic nanomedicines (Cu-CaO2@PDA/PM). The as-fabricated Cu-CaO2@PDA/PM multifunctional nanomedicines could decompose within the tumor microenvironment to release Ca2+ for ion interference therapy, and the generated H2O2 could perform a Fenton-like reaction with the assistance of loaded copper ions to produce ·OH, thus realizing chemodynamic therapy. In addition, the copper ions could also consume glutathione and weaken its ability to scavenge reactive oxygen species, which was conducive to amplifying the effect of oxidative stress. The coating of the polydopamine layer could achieve local hyperthermia of the tumor site, and the surface modification of the platelet membrane could enhance the targeting and biocompatibility of nanomedicines. In vivo and in vitro tests demonstrated that the developed Cu-CaO2@PDA/PM biomimetic nanomedicines offer a promising biomimetic nanoplatform for efficient multimodal combination therapy for breast cancer.

A Multifunctional Low-Temperature Photothermal Nanomedicine for Melanoma Treatment via the Oxidative Stress Pathway Therapy.

Melanoma is a highly aggressive and dangerous malignant skin tumor and there is an urgent need to develop effective therapeutic approaches against melanoma. The main objective of this study was to construct a multifunctional nanomedicine (GNR@PEG-Qu) to investigate its therapeutic effect on melanoma from the oxidative stress pathway. First, the nanomedicine GNR@PEG-Qu was synthesized and characterized, and its photothermal and antioxidant properties were confirmed. In addition, in vivo imaging capabilities were observed. Finally, the tumor inhibitory effects of GNR@PEG-Qu in vivo and in vitro as well as its biosafety were observed. GNR@PEG-Qu shows good photothermal and anti-oxidation properties. Following exposure to 1064 nm laser irradiation in the second near-infrared II (NIR-II) window, GNR@PEG-Qu shows anti-tumor ability through low-temperature photothermal therapy (PTT) adjuvant drug chemotherapy. GNR@PEG-Qu makes full use of the antioxidant capacity of quercetin, reduces ROS levels in melanoma, alleviates oxidative stress state, and achieves "oxidative stress avoidance" at the tumor site. Quercetin can also downregulate the expression of the heat shock protein Hsp70, which will improve the thermal sensitivity of the tumor site and enhance the efficacy of low-temperature PTT. GNR@PEG-Qu nanoagent exhibits synergistic treatment and high tumor inhibition effects, which is a promising strategy developed to achieve oxidative stress avoidance and synergistic therapy of melanoma using quercetin (Qu)-coated gold nanorod (GNR@PEG).

Self-assembly nanomedicine initiating cancer-immunity cycle with cascade reactions for boosted immunotherapy

Immune checkpoint blockade (ICB) therapy has been extensively integrated into cancer clinical management. However, its overall response rate is limited due to the stagnating cancer-immunity cycle (CIC) caused by the immunosuppressive tumor microenvironment (TME). Here, a multi-pronged nanomedicine, defined as LCCS, was constructed by the self-assembly of lactate oxidase, catalase, chlorin e6, and sorafenib. Through cascade reactions, LCCS effectively reprogrammed the TME and re-initiated the CIC by depleting lactate, alleviating hypoxia, inducing immunogenic cell death, and normalizing tumor vessels. Immunological analyses indicated that treatment with LCCS decreased the infiltration of immunosuppressive cells while increasing the recruitment of immune effector cells in tumors. Leveraging the effective operation of the CIC, LCCS improved the efficacy of ICB therapy to inhibit breast cancer, and effectively induced the elimination of colorectal cancer and long-term immune memory. Therefore, multifunctional nanomedicines targeting CIC hold great potential for applications in cancer immunotherapy.

Oral Administration of Bioactive Nanoparticulates for Inflammatory Bowel Disease Therapy by Mitigating Oxidative Stress and Restoring Intestinal Microbiota Homeostasis.

The management of inflammatory bowel disease (IBD) continues to pose significant challenges due to the absence of curative therapies and a high rate of recurrence. Therefore, it is imperative to explore novel approaches to enhance the efficacy of IBD therapy. Herein, a bioactive nanoparticulate s is tailored designed to achieve a "Pull-Push" approach for efficient and safe IBD treatment by integrating reactive oxygen species (ROS) scavenging (Pull) with anti-inflammatory agent delivery (Push) in the inflammatory microenvironment. The multifunctional nanomedicine, designated MON-PAMAM@SASP, is developed through the encapsulation of sulfasalazine (SASP), a widely utilized clinical drug for the treatment of IBD, within cationic diselenide-bridged mesoporous organosilica nanoparticles (MONs) that possess significant antioxidant properties. Herein, poly(amidoamine) (PAMAM) endows the original MONs with positive charge characteristics. The MON-PAMAM@SASP not only displays the remarkable capability of neutralizing ROS to ameliorates intestinal damage, but also achieves controllable release of SASP to mitigate intestinal inflammation. Consequently, this nanomedicine effectively mitigates IBD by colitis in mouse models, and our current research has not identified any significant drug toxicity. Beyond regulating inflammatory microenvironment in intestine, treatment with MON-PAMAM@SASP results in increased richness and restores intestinal microbiota homeostasis, thereby mitigating IBD to a certain extent. Together, our work provides a highly versatile "Pull-Push" approach for IBD management and encourages the development of similar nanomedicine to treating multiple inflammatory diseases of gastrointestinal tract.

Colostrum-derived extracellular vesicles: potential multifunctional nanomedicine for alleviating mastitis

Bovine mastitis is an infectious disease that causes substantial economic losses to the dairy industry worldwide. Current antibiotic therapy faces issues of antibiotic misuse and antimicrobial resistance, which has aroused concerns for both veterinary and human medicine. Thus, this study explored the potential of Colo EVs (bovine colostrum-derived extracellular vesicles) to address mastitis. Using LPS-induced murine mammary epithelial cells (HC11), mouse monocyte macrophages (RAW 264.7), and a murine mastitis model with BALB/C mice, we evaluated the safety and efficacy of Colo EVs, in vivo and in vitro. Colo EVs had favorable biosafety profiles, promoting cell proliferation and migration without inducing pathological changes after injection into murine mammary glands. In LPS-induced murine mastitis, Colo EVs significantly reduced inflammation, improved inflammatory scores, and preserved tight junction proteins while protecting milk production. Additionally, in vitro experiments demonstrated that Colo EVs downregulated inflammatory cytokine expression, reduced inflammatory markers, and attenuated NF-κB pathway activation. In summary, we inferred that Colo EVs have promise as a therapeutic approach for mastitis treatment, owing to their anti-inflammatory properties, potentially mediated through the NF-κB signaling pathway modulation.Graphical

Carrier-free multifunctional nanomedicine for enhanced hyperthermic intraperitoneal chemotherapy against abdominal pelvic tumors

Hyperthermic intraperitoneal chemotherapy (HIPEC) as an innovative approach in cancer therapy can deliver heated drugs directly into the abdominal cavity. Nevertheless, HIPEC also promotes upregulation of heat shock proteins, potentially leading to resistance against hyperthermia. Herein, novel nanoparticles self-assembled from gambogic acid (GA) and metformin (Met) are prepared through multiple interactions, enabling HIPEC for the treatment of orthotopic colorectal and ovarian cancers. Briefly, mild heat (abbreviated as MH) triggers immunogenic cell death (ICD) of cancer cells, leading to the release of damage-associated molecular patterns (DMAPs) that boost the immunogenicity of tumor microenvironment. GA, a potent inhibitor of heat shock protein (HSP-90), increases the sensitivity of cancer cells to hyperthermia-induced cell death. Moreover, GA acts as a chemotherapeutic agent itself, effectively inducing apoptosis of cancer cells and amplifying the ICD induced by MH. Met, can efficiently clear the tumor extracellular matrixes to facilitate the deeper penetration of nanoparticles into tumor tissues and promotes the infiltration of cytotoxic T lymphocytes. More importantly, the synergistic combination of GA and Met during HIPEC triggers a robust anti-tumor immune response in vivo. This integrated strategy offers a promising therapeutic avenue for the management of advanced abdominal pelvic tumor, possessing the potential for broad clinical applications.

Doxorubicin-Intercalated Li-Al-Based LDHs as Potential Drug Delivery Nanovehicle with pH-Responsive Therapeutic Cargo for Tumor Treatment.

Clinical oncology is currently experiencing a technology bottleneck due to the expeditious evolution of therapy defiance in tumors. Although drugs used in chemotherapy work for a sort of cell death with potential clinical application, the effectiveness of chemotherapy-inducing drugs is subject to several endogenous conditions when used alone, necessitating the urgent need for controlled mechanisms. A tumor-targeted drug delivery therapy using Li-Al (M+/M3+)-based layered double hydroxide (LDHs) family has been proposed with the general chemical formula [M+1-x M3+x (OH)]2x+[(Am-)2x/m. n(H2O)]2x-, which is fully biodegradable and works in connection with the therapeutic interaction between LDH nanocarriers and anticancerous doxorubicin (DOX). Compositional variation of Li and Al in LDHs has been used as a nanoplatform, which provides a functional balance between circulation lifetime, drug loading capacity, encapsulation efficiency, and tumor-specific uptake to act as self-regulatory therapeutic cargo to be released intracellularly. First-principle analyses based on DFT have been employed to investigate the interaction of bonding and electronic structure of LDH with DOX and assess its capability and potential for a superior drug carrier. Following the internalization into cancer cells, nanoformulations are carried to the nucleus via lysosomes, and the mechanistic pathways have been revealed. Additionally, in vitro along with in vivo therapeutic assessments on melanoma-bearing mice show a dimensional effect of nanoformulation for better biocompatibility and excellent synergetic anticancer activity. Further, the severe toxic consequences associated with traditional chemotherapy have been eradicated by using injectable hydrogel placed just beneath the tumor site, and regulated release of the drug has been confirmed through protein expression applying various markers. However, Li-Al-based LDH nanocarriers open up new design options for multifunctional nanomedicine, which has intriguing potential for use in cancer treatment through sustained drug delivery.

Ferroptosis-inducing nanomedicine and targeted short peptide for synergistic treatment of hepatocellular carcinoma

The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.

Self-assembled metal-polyphenolic based multifunctional nanomedicine to improve therapy treatment of pancreatic cancer by inhibition of glutamine metabolism

Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.

Predicting anti-tumor efficacy of multi-functional nanomedicine on decellularized hepatocellular carcinoma-on-a-chip

Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe3O4)-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening.

Dopamine and Citicoline-Co-Loaded Solid Lipid Nanoparticles as Multifunctional Nanomedicines for Parkinson's Disease Treatment by Intranasal Administration.

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application.

Unprecedented Organogermanium Functionalized GeIV-SbIII-Templating Polyoxotungstate Nanocluster for Photothermal-Chemodynamic Cancer Therapy.

The function-oriented synthesis of polyoxometalate (POM) nanoclusters has become an increasingly important area of research. Herein, the well-known broad-spectrum anticancer drug Ge-132 which contains GeIV as potential heteroatoms and carboxyl coordination sites, is introduced to the POM system, leading to the first organogermanium functionalized GeIV-SbIII-templating POM nanocluster Na4[H2N(CH3)2]16 H18[Sm4(H2O)12W4O14Ge(CH2CH2COOH)]2[SbW9O33]4[Ge(CH2CH2COOH) SbW15O54]2·62H2O (1). An unprecedented organogermanium templating Dawson-like [Ge(CH2CH2COOH)SbW15O54]12- building block is discovered. To take advantage of the potential pharmaceutical activity of such an organogermanium-functionalized POM cluster, 1 is further composited with gold nanoparticles (NPs) to prepare 1-Au NPs, which doubles the blood circulation time of 1-based nanodrug. Efficient separation of photogenerated charges in 1-Au NPs largely boosts the photothermal conversion efficiency (PCE=55.0%), which is nearly 2.1 times that of either single 1 (PCE=26.7%) or Au NPs (PCE=26.2%), and simultaneously facilitate the generation of toxic activate reactive oxygen species in tumor microenvironment. Based on these findings, it is demonstrated that 1-Au NPs are a multifunctional and renal clearable nanomedicine with great potential in photoacoustic imaging guiding photothermal-chemodynamic therapy for breast cancer.

Perovskite-structured ultrasensitive CaMnO3 nanoenzyme enables highly efficient ultrasound-amplified and catalysis-involved synergistic tumor therapy

Catalytic nanoenzyme-mediated therapy with reactive oxygen species generation feature and tumor microenvironment regulation characteristic has demonstrated high therapeutic efficacy in oncological field, whereas its low enzyme-mimicking reaction efficacy typically results in dissatisfied therapeutic effect and outcome. Herein, an ultrasensitive CaMnO3 (CMO) nanoenzyme has been rationally designed and engineered for enzyodynamic-calcium overload synergistic tumor therapy. CMO nanoenzyme with oxidase (OXD)-, peroxidase (POD)- and glutathione peroxidase (GPx)-mimic activities is responsible for the generation of reactive oxygen species, the consumption of intra-tumor glutathione and mitochondrial damage. For the evaluation of OXD and POD-mimicking activities, CMO with ultra low concentration (1 μg ml−1) can rapidly catalyze the color reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) hydrochloride and reach the reaction termination in a very short time (1 s). Moreover, the release and overload of Ca2+ strengthen the tumor cell death. Exogenous ultrasound stimulation further amplifies the enzyodynamic-Ca2+ overload synergistic tumor-therapeutic efficacy. In vitro and in vivo results affirm the transcendent antineoplastic outcomes of CMO. Meanwhile, the existence of Mn2+ endows nanoenzyme with T1-weighted MR imaging capacity. This work provides new strategies for efficient enzyme-mimicking activity and tumor synergistic treatment based on new perspectives on the engineering of multifunctional therapeutic nanomedicine.

Synthesis of two Fluorescent Complexes and Their use as Multifunctional Nanomedicine Carriers for Rhabdomyosarcoma Treatment.

This study focuses on the design and synthesis of two novel coordination polymers (CPs), named 1 and 2, with excellent fluorescent properties. Their structures were characterized by X-ray single-crystal diffraction, revealing that both materials exhibit promising fluorescence performance, indicating their potential as fluorescent detection tools. Additionally, 1 was chosen to be combined with chitosan (CS), resulting in the successful fabrication of a biodegradable and non-toxic efficient drug carrier, termed CS-1@Cisplatin. This carrier possesses a large surface area and good solubility, enabling sustained drug release to target cells. Given that CXC motif chemokine receptor type 4 (CXCR4) is a key marker gene highly expressed in Rhabdomyosarcoma (RMS) cells and tissues, RMS was chosen as the biological model for testing. The results demonstrated that CS-1@Cisplatin effectively inhibited the invasiveness of RMS cells by significantly suppressing CXCR4 expression. Therefore, the system shows great potential for applications in RMS treatment, biometrics, and drug delivery, particularly in its unique advantage of targeting RMS by inhibiting the key marker gene CXCR4.

Aptamer-Modified Nb2C Multifunctional Nanomedicine for Targeted Photothermal/Chemotherapy Combined Therapy of Tumor.

The poor delivery efficiency of nanotherapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. An active targeting system with high efficiency and few side effects is a promising strategy for tumor therapy. Herein, a multifunctional nanomedicine Nb2C-PAA-DOX@Apt-M (NDA-M) was constructed for targeted photothermal/chemotherapy (PTT/CHT) combined tumor therapy. The specific targeting ability of aptamer could effectively enhance the absorption of nanomedicine by the MCF-7 cell. By employing Apt-M, the NDA-M nanosheets demonstrated targeted delivery to MCF-7 cells, resulting in enhanced intracellular drug concentration. Under 1060 nm laser irradiation, a rapid temperature increase of the NDA-M was observed within the tumor region to achieve PTT. Meanwhile, CHT was triggered when DOX release was induced by photothermal/acid stimulation. The experimental results demonstrated that aptamer-mediated targeting achieved enhanced PTT/CHT efficacy both in vitro and in vivo. Notably, NDA-M induced complete ablation of solid tumors without any adverse side effects in mice. This study demonstrated new and promising tactics for the development of nanomaterials for targeted tumor therapy.

Glycooligomer-Functionalized Catalytic Nanocompartments Co-Loaded with Enzymes Support Parallel Reactions and Promote Cell Internalization.

A major shortcoming associated with the application of enzymes in drug synergism originates from the lack of site-specific, multifunctional nanomedicine. This study introduces catalytic nanocompartments (CNCs) made of a mixture of PDMS-b-PMOXA diblock copolymers, decorated with glycooligomer tethers comprising eight mannose-containing repeating units and coencapsulating two enzymes, providing multifunctionality by their in situ parallel reactions. Beta-glucuronidase (GUS) serves for local reactivation of the drug hymecromone, while glucose oxidase (GOx) induces cell starvation through glucose depletion and generation of the cytotoxic H2O2. The insertion of the pore-forming peptide, melittin, facilitates diffusion of substrates and products through the membranes. Increased cell-specific internalization of the CNCs results in a substantial decrease in HepG2 cell viability after 24 h, attributed to simultaneous production of hymecromone and H2O2. Such parallel enzymatic reactions taking place in nanocompartments pave the way to achieve efficient combinatorial cancer therapy by enabling localized drug production along with reactive oxygen species (ROS) elevation.

Niobium carbide MXenzyme-Driven comprehensive cholesterol regulation for photoacoustic image-guided and anti-inflammatory photothermal ablation in atherosclerosis

Foam cells play a pivotal role in the progression of atherosclerosis progression by triggering inflammation within arterial walls. They release inflammatory molecules that attract additional immune cells, leading to further macrophage recruitment and plaque development. In this study, we develop an osteopontin (OPN) antibody-conjugated niobium carbide (Nb2C-aOPN) MXenzyme designed to selectively target and mildly ablate foam cells while reducing inflammation in the plaque microenvironment. This approach utilizes photonic hyperthermia to decrease plaque size by enhancing cholesterol regulation through both passive cholesterol outflow and positive cholesterol efflux. Nb2C-aOPN MXenzyme exhibits multiple enzyme-mimicking properties, including catalase, superoxide dismutase, peroxidase and glutathione peroxidase, and acts as a scavenger for reactive oxygen and nitrogen species. The inhibition of reactive oxygen and nitrogen species synergizes with photothermal ablation to promote positive cholesterol efflux, leading to reduced macrophage recruitment and a shift in macrophage phenotype from M1 to M2. This integrative strategy on cholesterol regulation and anti-inflammation highlights the potential of multifunctional 2D MXenzyme-based nanomedicine in advancing atherosclerotic regression.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Dual regulation of the orderly aggregation of covalent organic frameworks at the molecular level and nanoscale to achieve efficient phototherapy and gene therapy

Numerous studies have established the promise of combining phototherapy and gene therapy. However, there are persistent obstacles hindering the full optimization of this combined therapeutic approach, such as the maximum development of photosensitizers and the construction of high-performance gene carriers. The LEGO stacking characteristics of COFs have brought infinite imagination to the construction of delivery systems, allowing for the design of responsive nano castles based on different application scenarios. Here, we have constructed a novel cationic multifunctional nano COF nucleic acid delivery system based on photosensitizer and cationic monomers. The long-range ordered structure of COF effectively regulates the spatial distribution of photosensitizer, thereby preserving their phototherapy efficacy. Simultaneously, the inherent cationic porous nanostructure equips COF with exceptional capabilities for delivering nucleic acids. This integrated multifunctional nano delivery system significantly enhances the combined efficacy of phototherapy and gene therapy. The phototherapy capacity of COF enables precise tumor elimination in a spatiotemporal manner, inducing robust ICD and activating immune cells at the tumor site. Furthermore, loaded siPD-L1 significantly enhances immune cell recognition and killing of tumor cells, effectively shielding mice from re-invasion and tumor metastasis. The development of multifunctional nanomedicine based on COF provides new ideas for efficient tumor combination therapy.

Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.