Nanomedicine Platform Research Articles

Synergistic Potential of Nanomedicine in Prostate Cancer Immunotherapy: Breakthroughs and Prospects.

Given the global prevalence of prostate cancer in men, it is crucial to explore more effective treatment strategies. Recently, immunotherapy has emerged as a promising cancer treatment due to its unique mechanism of action and potential long-term effectiveness. However, its limited efficacy in prostate cancer has prompted renewed interest in developing strategies to improve immunotherapy outcomes. Nanomedicine offers a novel perspective on cancer treatment with its unique size effects and surface properties. By employing targeted delivery, controlled release, and enhanced immunogenicity, nanoparticles can be synergized with nanomedicine platforms to amplify the effectiveness of immunotherapy in treating prostate cancer. Simultaneously, nanotechnology can address the limitations of immunotherapy and the challenges of immune escape and tumor microenvironment regulation. Additionally, the synergistic effects of combining nanomedicine with other therapies offer promising clinical outcomes. Innovative applications of nanomedicine include smart nanocarriers, stimulus-responsive systems, and precision medicine approaches to overcome translational obstacles in prostate cancer immunotherapy. This review highlights the transformative potential of nanomedicine in enhancing prostate cancer immunotherapy and emphasizes the need for interdisciplinary collaboration to drive research and clinical applications forward.

Microfluidic-Derived Docosahexaenoic Acid Liposomes for Targeting Glioblastoma and Its Inflammatory Microenvironment.

Glioblastoma (GBM) is the most common malignant primary brain tumor, characterized by limited treatment options and a poor prognosis. Its aggressiveness is attributed not only to the uncontrolled proliferation and invasion of tumor cells but also to the complex interplay between these cells and the surrounding microenvironment. Within the tumor microenvironment, an intricate network of immune cells, stromal cells, and various signaling molecules creates a pro-inflammatory milieu that supports tumor growth and progression. Docosahexaenoic acid (DHA), an essential ω3 polyunsaturated fatty acid for brain function, is associated with anti-inflammatory and anticarcinogenic properties. Therefore, in this work, DHA liposomes were synthesized using a microfluidic platform to target and reduce the inflammatory environment of GBM. The liposomes were rapidly taken up by macrophages in a time-dependent manner without causing cytotoxicity. Moreover, DHA liposomes successfully downregulated the expression of inflammatory-associated genes (IL-6; IL-1β; TNFα; NF-κB, and STAT-1) and the secretion of key cytokines (IL-6 and TNFα) in stimulated macrophages and GBM cells. Conversely, no significant differences were observed in the expression of IL-10, an anti-inflammatory gene expressed in alternatively activated macrophages. Additionally, DHA liposomes were found to be more efficient in regulating the inflammatory profile of these cells compared with a free formulation of DHA. The nanomedicine platform established in this work opens new opportunities for developing liposomes incorporating DHA to target GBM and its inflammatory milieu.

Magnetic/Acoustic Dual-Controlled Microrobot Overcoming Oto-Biological Barrier for On-Demand Multidrug Delivery against Hearing Loss.

Multidrug combination therapy in the inner ear faces diverse challenges due to the distinct physicochemical properties of drugs and the difficulties of overcoming the oto-biologic barrier. Although nanomedicine platforms offer potential solutions to multidrug delivery, the access of drugs to the inner ear remains limited. Micro/nanomachines, capable of delivering cargo actively, are promising tools for overcoming bio-barriers. Herein, a novel microrobot-based strategy to penetrate the round window membrane (RWM) is presented and multidrug in on-demand manner is delivered. The tube-type microrobot (TTMR) is constructed using the template-assisted layer-by-layer (LbL) assembly of chitosan/ferroferric oxide/silicon dioxide (CS/Fe3O4/SiO2) and loaded with anti-ototoxic drugs (curcumin, CUR and tanshinone IIA, TSA) and perfluorohexane (PFH). Fe3O4 provides magnetic actuation, while PFH ensures acoustic propulsion. Upon ultrasound stimulation, the vaporization of PFH enables a microshotgun-like behavior, propelling the drugs through barriers and driving them into the inner ear. Notably, the proportion of drugs entering the inner ear can be precisely controlled by varying the feeding ratios. Furthermore, in vivo studies demonstrate that the drug-loaded microrobot exhibits superior protective effects and excellent biosafety toward cisplatin (CDDP)-induced hearing loss. Overall, the microrobot-based strategy provides a promising direction for on-demand multidrug delivery for ear diseases.

Construction of biomimetic camouflaged neutrophil membrane nanoparticles for precise delivery and augmented glioma cancer treatment

Developing novel nanomedicine formulations that successfully penetrate the blood-brain barrier (BBB) to treat and diagnose glioma effectively is still a significant obstacle. This study presents the development of polymer nanogels camouflaged with macrophage membranes. The nanogels are loaded with manganese dioxide (MnO2) and carboplatin. They are designed for the treatment of glioma using a combination of chemotherapy and chemodynamic therapy (CDT). The precipitation polymerization process was used to create redox-responsive poly(caprolactone) (PCL) nanogels (NGs). These NGs were then loaded with MnO2 and physically encapsulated with carboplatin. The resulting nanogels had an average diameter of 102.52 nm and were covered with macrophage membranes to provide excellent stability. The developed NGs exhibit redox and pH responsiveness, releasing carboplatin and Mn(II) in a controlled manner. NGs may effectively deplete glutathione (GSH) in the tumour milieu. The Mn(II) generated in this process enhances the effectiveness of the loaded carboplatin by exerting its chemotherapeutic action and promoting the formation of reactive oxygen species to improve the efficiency of CDT. The results of our study show a very efficient and promising nanomedicine platform for the treatment and diagnosis of glioma, a type of cancer. This platform is self-adaptive, cooperative, and based on NG technology. Furthermore, this platform can potentially be used for other challenging types of cancer.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs’ half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. Statement of significanceTreatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Generation of anti-SN38 antibody for loading efficacy and therapeutic monitoring of SN38-containing therapeutics

SN38, one of the most potent anti-tumor analogues of the camptothecins (CPTs), has limitations in its direct formulation as an anticancer agent due to its super toxicity and poor solubility in water and pharmaceutically approved solvents. However, it has garnered significant scientific interest as a payload in conjugated nanomedicine platforms (e.g., SN-38lip, NK012, SNB-101, and ADCs) to enhance their effectiveness and safety. The development of these platforms necessitates a convenient quantitative determination of SN38 in preclinical and clinical studies, a need that our study directly addresses, offering a practical solution to a pressing problem in cancer research and drug development. This study details the meticulous process of generating poly and monoclonal antibodies (pAb and mAb) against SN38 and their application to measure the SN38 in naked and conjugated forms of SN38-conjugated ADCs. For this purpose, two haptens of SN38 were synthesized by introducing the glycine or 4-amino-4-oxobutanyol(glycine) moiety as a conjugation functional group of the SN38. IR, NMR and mass spectrometric techniques confirmed the chemical modifications of the haptens. The haptens were then conjugated to each bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH) protein. The SN38-KLH conjugates were meticulously examined for immunization and generation of pAb and mAb. The immunization efficiency, reactivity, binding affinity, specificity, and cross-reactivity of purified pAb and mAb against Irinotecan, a model for the emergence of an SN38 derivative in clinical settings, were evaluated using ELISA and western blotting (WB) techniques. Conjugation efficiency of the SN38 to the KLH was increased using 4-amino-4-oxobutanyol(glycine) moiety, as its immunization efficacy was more to generate pAb. Furthermore, only this hapten could immunized mice to generate mAb recognizing SN38 with nanomolar equilibrium affinity. Our recent findings strongly support the notion that the generated pAb employed in developing an ELISA effectively ascertains the presence of SN38 in SN38-conjugated ADC, with a test midpoint EC50 of 2.5 μg/mL.Our study's unique contribution to the field lies in the development of specific antibodies against SN38 for measuring it on ADC, a feat that has not been achieved before. These immunoassays can be readily applied to detect other SN38-conjugate therapeutic platforms, thereby enhancing their clinical knowledge translation. The affinity of both pAb and mAb also meets the acceptance criteria for quantifying SN38 in fluidic material, as well as in Therapeutic drug monitoring (TDM) studies, a crucial aspect of personalized medicine. The potential applications of the anti-SN38 antibodies extend to reducing SN38-induced systemic toxicity through an inverse targeting strategy, a novel approach that piques further interest in our findings.

Spatiotemporal Concurrent PARP Inhibitor Sensitization Based on Radiation-Responsive Nanovesicles for Lung Cancer Chemoradiotherapy.

The implementation of chemoradiation combinations has gained great momentum in clinical practices. However, the full utility of this paradigm is often restricted by the discordant tempos of action of chemotherapy and radiotherapy. Here, a gold nanoparticle-based radiation-responsive nanovesicle system loaded with cisplatin and veliparib, denoted as CV-Au NVs, is developed to augment the concurrent chemoradiation effect in a spatiotemporally controllable manner of drug release. Upon irradiation, the in situ generation of •OH induces the oxidation of polyphenylene sulfide from being hydrophobic to hydrophilic, resulting in the disintegration of the nanovesicles and the rapid release of the entrapped cisplatin and veliparib (the poly ADP-ribose polymerase (PARP) inhibitor). Cisplatin-induced DNA damage and the impairment of the DNA repair mechanism mediated by veliparib synergistically elicit potent pro-apoptotic effects. In vivo studies suggest that one-dose injection of the CV-Au NVs and one-time X-ray irradiation paradigm effectively inhibit tumor growth in the A549 lung cancer model. This study provides new insight into designing nanomedicine platforms in chemoradiation therapy from a vantage point of synergizing both chemotherapy and radiation therapy in a spatiotemporally concurrent manner.

Review on Hyaluronic Acid Functionalized Sulfur and Nitrogen Co-Doped Graphene Quantum Dots Nano Conjugates for Targeting of Specific Type of Cancer.

Many people lose their lives to cancer each year. The prevalence of illnesses, metabolic disorders, high-risk infections, and other conditions has been greatly slowed down by expanding scientific research. Chemotherapy and radiation are still the initial lines of treatment for cancer patients, along with surgical removal of tumors. Modifications have been made in chemotherapy since medicines frequently have substantial systemic toxicity and poor pharmacokinetics and still do not reach the tumor site at effective concentrations. Chemotherapy may now be administered more safely and effectively thanks to nanotechnology. Nanotechnology-based graphene quantum dots (GQDs) are very applicable in breast cancer detection, as a drug delivery system, and in the treatment of breast cancer because of their physical and chemical properties, lower toxicity, small size, fluorescence, and effective drug delivery. This paper analyzes the GQDs as cutting-edge platforms for biotechnology and nanomedicine also its application in drug delivery in cancer. It shows that GQDs can be effectively conjugated with hyaluronic acid (HA) to achieve efficient and target-specific delivery.

Recent updates in applications of nanomedicine for the treatment of hepatic fibrosis.

Over recent decades, nanomedicine has played an important role in the enhancement of therapeutic outcomes compared to those of conventional therapy. At the same time, nanoparticle drug delivery systems offer a significant reduction in side effects of treatments by lowering the off-target biodistribution of the active pharmaceutical ingredients. Cancer nanomedicine represents the most extensively studied nanotechnology application in the field of pharmaceutics and pharmacology since the first nanodrug for cancer treatment, liposomal doxorubicin (Doxil®), has been approved by the FDA. The advancement of cancer nanomedicine and its enormous technological success also included various other target diseases, including hepatic fibrosis. This confirms the versatility of nanomedicine for improving therapeutic activity. In this review, we summarize recent updates of nanomedicine platforms for improving therapeutic efficacy regarding liver fibrosis. We first emphasize the challenges of conventional drugs for penetrating the biological barriers of the liver. After that, we highlight design principles of nanocarriers for achieving improved drug delivery of antifibrosis drugs through passive and active targeting strategies.

Unveiling the anti-cancer, anti-inflammatory, anti-oxidant and anti-bacterial properties of in situ phyto-fabricated silver nanoparticles: an in vitro approach

Phyto-fabricated nano-biomaterials like silver nanoparticles (Ag NPs) possess the potential to serve as smart nanomedicine platforms for the medical assessment and treatment of a diverse array of diseases including cancer and infectious ones.

A functionalized cell membrane biomimetic nanoformulation based on layered double hydroxide for combined tumor chemotherapy and sonodynamic therapy.

The development of nanoformulations with simple compositions that can exert targeted combination therapy still remains a great challenge in the area of precision cancer nanomedicine. Herein, we report the design of a multifunctional nanoplatform based on methotrexate (MTX)-loaded layered double hydroxide (LDH) coated with chlorin e6 (Ce6)-modified MCF-7 cell membranes (CMM) for combined chemo/sonodynamic therapy of breast cancer. LDH nanoparticles were in situ loaded with MTX via coprecipitation, and coated with CMM that were finally functionalized with phospholipid-modified Ce6. The created nanoformulation of LDH-MTX@CMM-Ce6 displays good colloidal stability under physiological conditions and can release MTX in a pH-dependent manner. We show that the formulation can homologously target breast cancer cells, and induce their significant apoptosis through arresting the cell cycle via cooperative MTX-based chemotherapy and ultrasound (US)-activated sonodynamic therapy. The assistance of US can not only trigger sonosensitizer Ce6 to produce reactive oxygen species, but also enhance the cellular uptake of LDH-MTX@CMM-Ce6 via an acoustic cavitation effect. Upon intravenous injection and US irradiation, LDH-MTX@CMM-Ce6 displays an admirable antitumor performance towards a xenografted breast tumor mouse model. Furthermore, the modification of Ce6 on the CMM endows the LDH-based nanoplatform with fluorescence imaging capability. The developed LDH-based nanoformulation here provides a general intelligent cancer nanomedicine platform with simple composition and homologous targeting specificity for combined chemo/sonodynamic therapy and fluorescence imaging of tumors.

Supramolecular nanoparticles based on elastin-like peptides modified capsid protein as drug delivery platform with enhanced cancer chemotherapy efficacy

Cancer, a prevalent disease posing significant threats to human health and longevity, necessitates effective therapeutic interventions. Chemotherapy has emerged as a primary strategy following surgical procedures for combating most malignancies. Despite the considerable efficacy of conventional chemotherapeutic agents against cancer cells, their utility is hindered by profound challenges such as multidrug resistance and deleterious toxic side effects, thereby limiting their systemic application. To tackle these challenges, we have devised a promising nanomedicine platform based on a plant virus. Specifically, we have selected the cowpea melanoma mottled virus (CCMV) as our nano-delivery system owing to its monodisperse and homogeneous size, as well as its intrinsic ability for controlled self-assembly. Leveraging the potential of this platform, we have engineered CCMV-based nanoparticles functionalized with elastin-like peptides (ELPs) at their N-terminal region. The target protein, CP-ELP, was expressed via E.coli, enabling encapsulation of the model drug DOX upon structural domain modification of the protein. The resulting nanoparticles exhibit uniform size distribution, facilitating efficient internalization by tumor cells and subsequent intracellular drug release, leading to enhanced antitumor efficacy. In addition, EVLP@DOX nanoparticles were found to activate immune response of tumor microenvironment in vivo, which further inhibiting tumor growth. Our designed nanoparticles have also demonstrated remarkable therapeutic effectiveness and favorable biological safety profiles in both murine melanoma and colorectal cancer models.

Redox-responsive biodegradable dendronized polymers: A side-chain modulation based fabrication of drug delivery vehicles

Among various nanomedicine platforms, stimuli-responsive biodegradable polymeric micelles offer a viable approach to address challenges in cancer therapy. Herein, we report the fabrication of redox-responsive micellar aggregates based on an amphiphilic dendron-polymer conjugate. In particular, acid-degradable hydrophobic polyester dendrons are attached as side chain moieties through a disulfide linkage on a hydrophilic copolymer. Polymers containing three generations of dendrons are synthesized using the thiol-disulfide exchange reaction and utilized to obtain micellar aggregates. The stability of the obtained aggregates, drug loading, and release characteristics in neutral, acidic, and redox environments were investigated. It was established that micelles are efficiently internalized by cells, and the highest level of cytotoxicity was observed for MDA-MB-231 breast cancer carcinoma cells under a reducing environment.

Programming assembly of biomimetic exosomes: An emerging theranostic nanomedicine platform.

Exosomes have emerged as a promising cell-free therapeutic approach. However, challenges in large-scale production, quality control, and heterogeneity must be overcome before they can be used clinically. Biomimetic exosomes containing key components of natural exosomes have been assembled through extrusion, artificial synthesis, and liposome fusion to address these limitations. These exosome-mimetics (EMs) possess similar morphology and function but provide higher yields, faster large-scale production, and similar size compared to conventional exosomes. This article provides an overview of the chemical and biological properties of various synthetic exosome systems, including nanovesicles (NVs), EMs, and hybrid exosomes. We highlight recent advances in the production and applications of nanobiotechnology and discuss the advantages, limitations, and potential clinical applications of programming assembly of exosome mimetics.

Optically Controlled Dissolution Kinetics of Vaterite Microcapsules: Toward Novel Crystal Growth Strategies.

Controllable continuous release of functional materials from capsules is one of the unmet functions of theragnosis particles; on this way, understanding cargo-fluid interactions in vitro is an essential milestone. We develop a flexible platform to investigate single particle-fluid interactions utilizing a glass micropipette as a highly localized flow source around an optically trapped particle. In proof-of-concept experiments, this microparticle is sensitive to local microflow distribution, thus serving as a probe. The very same flows are capable of the particle rotating (i.e., vaterite drug cargo) at frequencies dependent on the mutual particle-pipette position. Platform flexibility comes from different interactions of a tweezer (optical forces) and a pipette (mechanical/hydrodynamical) with a microparticle, which makes this arrangement an ideal microtool. We studied the vaterite dissolution kinetics and demonstrated that it can be controlled on demand, providing a wide cargo release dynamic rate. Our results promote the use of inorganic mesoporous nanoparticles as a nanomedicine platform.

Microfluidic-derived docosahexaenoic acid liposomes for glioblastoma therapy

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor and currently lacks an effective treatment. In this study, we utilized a microfluidic system to synthesize docosahexaenoic acid (DHA) liposomes for GBM therapy. DHA is an omega-3 (ω3) polyunsaturated fatty acid commonly found in human dietary consumption that has demonstrated potential in mitigating cancer development. The microfluidic device employed allowed for precise fine-tuning of the physicochemical properties of liposomes by adjusting the flow rate ratios, flow rates, and lipid concentrations. Three distinct-sized liposomes, ranging from 80 nm and 130 nm, were successfully internalized by GBM cells, and demonstrated the ability to reduce the viability of these cells. Furthermore, DHA liposomes proved significantly more efficient in triggering apoptotic pathways, through caspase-3-dependent mechanisms, in comparison to free DHA. Thus, the nanomedicine platform established in this study presents new opportunities in the development of liposome formulations incorporating ω3 fatty acids for cancer therapy.

Synchronous targeted delivery of TGF-β siRNA to stromal and tumor cells elicits robust antitumor immunity against triple-negative breast cancer by comprehensively remodeling the tumor microenvironment

The poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)-β, an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF-β) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF-β small interference RNA (siTGF-β). It was determined that this system was able to improve the efficacy of anti-PD-L1. The siTGF-β nanosystem efficiently silenced TGF-β-related signaling pathways in both activated NIH 3T3 cells and 4T1 cells in vitro and in vivo. This occurred firstly, through CD44-mediated uptake, followed by rapid escape mediated by HAase in endo/lysosomes and release of siRNA mediated by high GSH concentrations in the cytoplasm. By simultaneous silencing of TGF-β in stromal and tumor cells, HA-LSL/siTGF-β dramatically reduced stroma deposition, promoted the penetration of nanomedicines for deep remodeling of the TME, improved oxygenation, T cells infiltration and subsequent anti-PD-L1 deep penetration. The double suppression of TGF-β has been demonstrated to promote blood vessel normalization, inhibit an epithelial-to-mesenchymal transition (EMT), and further modify the immunosuppressive TME, which was supported by an overall increase in the proportion of dendritic cells and cytotoxic T cells. Further, a reduction in the proportion of immunosuppression cells such as regulatory T cells and myeloid-derived suppressor cells was also observed in the TME. Based on the comprehensive remodeling of the tumor microenvironment by this nanosystem, subsequent anti-PD-L1 therapy elicited robust antitumor immunity. Specifically, this system was able to suppress the growth of both primary and distant tumor while preventing tumor metastasis to the lung. Therefore, the combination of the dual-targeted siTGF-β nanosystem, alongside anti-PD-L1 may serve as a novel method to enhance antitumor immunotherapy against stroma-rich TNBC.

Bioorthogonal CRISPR/Cas9-Drug Conjugate: A Combinatorial Nanomedicine Platform.

Bioconjugation of proteins can substantially expand the opportunities in biopharmaceutical development, however, applications are limited for the gene editing machinery despite its tremendous therapeutic potential. Here, a self-delivered nanomedicine platform based on bioorthogonal CRISPR/Cas9 conjugates, which can be armed with a chemotherapeutic drug for combinatorial therapy is introduced. It is demonstrated that multi-functionalized Cas9 with a drug and polymer can form self-condensed nanocomplexes, and induce significant gene editing upon delivery while avoiding the use of a conventional carrier formulation. It is shown that the nanomedicine platform can be applied for combinatorial therapy by incorporating the anti-cancer drug olaparib and targeting the RAD52 gene, leading to significant anti-tumor effects in BRCA-mutant cancer. The current development provides a versatile nanomedicine platform for combination treatment of human diseases such as cancer.

Hyaluronic acid-based supramolecular nanomedicine with optimized ratio of oxaliplatin/chlorin e6 for combined chemotherapy and O2-economized photodynamic therapy.

Dual- or multi-modality combination therapy has become one of the most effective strategies to overcome drug resistance in cancer therapy, and the optimized ratio of the therapeutic agents working on the tumor greatly affects the therapeutic outcomes. However, the absence of a facile method to optimize the ratio of therapeutic agents in nanomedicine has, at least in part, impaired the clinical potential of combination therapy. Herein, a new cucurbit[7]uril (CB[7])-conjugated hyaluronic acid (HA) based nanomedicine was developed, in which both chlorin e6 (Ce6) and oxaliplatin (OX) were co-loaded non-covalently at an optimized ratio via facile host-guest complexation, for optimal, combined photodynamic therapy (PDT)/chemotherapy. To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Additionally, HA on the surface of nanomedicine allowed targeted delivery to cancer cells with over-expressed CD44 receptors (such as CT26 cell lines). Thus, this supramolecular nanomedicine platform with an optimal ratio of photosensitizer and chemotherapeutic agent not only provides an important new tool for enhanced PDT/chemotherapy of solid tumors, but also offers a CB[7]-based host-guest complexation strategy to facilely optimize the ratio of therapeutic agents for multi-modality nanomedicine. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the most common modality for cancer treatment in clinical practice. Combination therapy by co-delivery of two or more therapeutic agents has been recognized as one of the most effective strategies to improve therapeutic outcome of cancer treatment. However, the ratio of loaded drugs could not be facilely optimized, which may greatly affect the combination efficiency and overall therapeutic outcome. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine.

Camouflaging multifunctional nanoparticles with bacterial outer membrane for augmented chemodynamic/photothermal/starvation/chemo multimodal synergistic therapy of orthotopic glioblastoma

Innovative therapeutic strategy and effective drug delivery are significant challenges in current glioblastoma multiforme (GBM) therapy. The development of efficient combination therapy based on chemodynamic therapy (CDT) has attracted widespread attention in recent years. Herein, a lipopolysaccharide-free bacterial outer membrane vesicles (dOMV) camouflaged biomimetic nanoreactor was constructed for quadruple synergistic therapy of orthotopic GBM. Benefiting from the immune escaping property and blood–brain barrier (BBB) penetration capacity of dOMV, nanoreactors can target cancer cells and accumulate in the tumor site. Firstly, for quadruple synergistic therapy, Glucose oxidase (GOx) can rapidly consume intratumoral glucose to generate H2O2 and gluconic acid for starvation therapy. Secondly, the abundant H2O2 produced by the enzyme-catalyzed reaction can continuously supply Cu9S8-mediated Fenton-like reaction to enhance CDT. Meanwhile, tumor hypoxic microenvironment exacerbated by GOx-induced oxygen depletion activated prodrug AQ4N for chemotherapy. Finally, the second near-infrared (NIR-II) absorbed Cu9S8 increased the temperature in local tumor site upon NIR-II laser irradiation, which can achieve photothermal-enhanced CDT, elevate GOx activity, and accelerate drug release. In vitro and in vivo results demonstrated that the camouflaging multifunctional nanoparticles with bacterial outer membrane (AG@Cu9S8@dOMV) was a promising multifunctional therapeutic nanomedicine platform for highly efficient treatment of GBM, which may be extended to as a treatment option for clinical cancer theranostics.