Responsive Nanosystems Research Articles

An Intelligent Triple Assisted Gold Cluster‐Based Nanosystem for Enhanced Tumor Photodynamic Therapy

Comprehensive SummaryPhotodynamic therapy (PDT) has been attracted a surge of research interest. However, there are several obstacles to limit the efficacy of PDT, such as hypoxic tumor microenvironment (TME), overexpressed glutathione (GSH), inefficient reactive oxygen species (ROS) generation, and so on. Herein, a smart responsive nanosystem was constructed, which was composed of Au25 modified with triphenylphosphine (Au25‐TPP), catalase (CAT) and GSH‐responsive diselenide‐bridged mesoporous silica nanoparticles (Se‐MSN). When the nanosystem arrived at tumor site, Se‐MSN was degraded by the intracellular overexpressed GSH to release Au25‐TPP and CAT. The Au25‐TPP was targeted to mitochondria and generated ROS under the 808 nm NIR laser irradiation to kill tumor cells. Simultaneously, CAT could catalyze hydrogen peroxide to provide oxygen for relieving the hypoxia of TME. Besides, GSH was consumed by the diselenide bond to diminish the ROS loss. The above tactics (mitochondria targeting, hypoxia relieving and GSH consuming) jointly enhanced the PDT efficacy. The nanosystem showed distinct in vitro anticancer effect significantly stronger than other groups containing one or two assistance. Moreover, the in vivo results suggested that the tumors could be restrained obviously. The current study provides a new inspiration for constructing novel inorganic nanomedicines with multiple enhancement effect of PDT efficacy.

NIR responsive nanosystem based on upconversion nanoparticle-engineered bacteria for immune/photodynamic combined therapy with bacteria self-clearing capability

Biological engineering bacteria hold great promise in tumor therapy due to their targeted delivery, tumor penetration, and tumor-specific activation capabilities. However, the use of live bacteria raises safety concerns, as they can potentially cause infections or adverse immune responses in patients. Additionally, most biological engineering bacteria are only responsive to blue light, which has limited penetration depth within biological tissues. To address these limitations, we have developed a nanoplatform that combines dual-emission upconversion nanoparticles (referred to as DDUCNPs), which can realize dual-wavelength emission under dual-wavelength excitation, with biological engineering bacteria for tumor treatment and the self-clearance of biological engineering bacteria after therapy in the near-infrared (NIR) window. This design allows us to utilize 980 nm light, which is converted to blue light by the DDUCNPs, to activate the bacteria and promote the controlled release of tumor necrosis factor-alpha (TNF-α) for precise tumor ablation. Subsequently, we employ 808 nm excitation to achieve light conversion into the red light, thereby activating photosensitizer molecules and generating singlet oxygen (ROS) for in vivo clearance of the bacteria involved in the treatment. Simultaneously, the generated ROS also undergoes photodynamic therapy (PDT) on the tumor to enhance the therapeutic effect. By combining these elements on a single platform, our system achieves the activation and self-clearance of biological engineering bacteria in the NIR window, effectively enabling tumor treatment. This approach overcomes the limitations of blue light penetration and addresses safety concerns associated with live bacteria, offering a promising strategy for precise and controlled tumor therapy.

Invasive metastatic tumor-camouflaged ROS responsive nanosystem for targeting therapeutic brain injury after cardiac arrest

Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation after cardiac arrest (CA-ROSC). Inspired by the propensity of melanoma metastasis to the brain, B16F10 cell membranes are camouflaged on 2-methoxyestradiol (2ME2)-loaded reactive oxygen species (ROS)-triggered “Padlock” nanoparticles that are constructed by phenylboronic acid pinacol esters conjugated D-a-tocopheryl polyethylene glycol succinate (TPGS-PBAP). The biomimetic nanoparticles (BM@TP/2ME2) can be internalized, mainly mediated by the mutual recognition and interaction between CD44v6 expressed on B16F10 cell membranes and hyaluronic acid on cerebral vascular endothelial cells, and they responsively release 2ME2 by the oxidative stress microenvironment. Notably, BM@TP/2ME2 can scavenge excessive ROS to reestablish redox balance, reverse neuroinflammation, and restore autophagic flux in damaged neurons, eventually exerting a remarkable neuroprotective effect after CA-ROSC in vitro and in vivo. This biomimetic drug delivery system is a novel and promising strategy for the treatment of cerebral ischemia-reperfusion injury after CA-ROSC.

Erythrocyte membrane-camouflaged nanodelivery strategy enhances gene editing efficiency of Cas9 RNP for boosting tumor senescence

CRISPR-Cas9 system has emerged as an effective tool for sequence-specific gene knockout through non-homologous end joining (NHEJ). However, the inefficient precise editing of genome sequences remains a challenge for clinical treatment. Herein, an erythrocyte membrane (EM)-camouflaged and tumor microenvironment (TME)-responsive nanosystem was constructed to achieve synergistic combination of enhanced Cas9 ribonucleoprotein (RNP) gene editing efficiency and telomere dysfunction, and thus precise induced tumor inhibition. The EM-camouflaged nanosystem escaped from the reticuloendothelial system (RES) and was endocytosed by tumor cells. Azidothymidine (AZT) was gradually released as the erythrocyte shell ablation, which competitively prevented the binding of single nucleotides to the telomere replication template TR, terminate the extension of the telomerase DNA chain. Additionally, Cas9 RNP was released through disulfide bond cleavage and entered into the nucleus to realize genome editing of telomerase reverse transcriptase (TERT) gene. Simultaneous, AZT enhanced NHEJ pathway to improve the gene editing efficiency of Cas9 RNP, which further promoted the progressive telomere erosion and thus induced tumor inhibition. Overall, this biomembrane-camouflaged nanosystem realizes enhanced Cas9 RNP gene editing efficiency with high-level biosafety and promotes tumor senescence by triggering telomere disorder, which provides strategy for improving the gene editing efficiency to induce senescence of tumor cells.

UV/esterase dual responsive nanosystems based on protoporphyrin IX-polyethylene glycol monomethyl ether for enhanced photodynamic bactericidal and herbicidal effects

Photoactivated pesticides with high activity, environmental friendliness, and no drug resistance represent the direction of pesticide development. However, poor photostability and lack of targeting ability greatly restrict their practical application. Herein, a novel amphiphilic photoactivated polymeric propesticide was synthesized by conjugation of mPEG with the photo/enzyme-labile o-nitrobenzyl ester group followed by grafting protoporphyrin IX (PpIX), which could self-assemble into photo/esterase responsive polymer micelles in aqueous solutions for a controlled release of PpIX. The fluorescence quenching caused by the aggregation of PpIX into hydrophobic core could enhance its photostability. UV/esterase stimulation could trigger the release of PpIX and restore its photodynamic activity. Compared to a single stimulus, dual stimulation could trigger more PpIX release and resulting in higher photodynamic activity and antibacterial effect. In addition, light exposure also showed little influence on the photodynamic activity and antibacterial effect of the system due to enhanced photostability. Compared with PpIX, the nanosystem exhibited higher wettability and retention ability on plant leaves and could resist rainwater washout. Weed control experiment also demonstrated that the system’s control effect on barnyard grass. Therefore, this study provides new ideas for promoting the application of photoactivated pesticides in the field of plant protection.

The conceptual design of pH responsive ZnO-adamantane nanosystems for insulin amyloidosis

Adamantane derivatives are already being explored in amyloidogenic diseases, while ZnO nanoparticles (NPs) have the potential for affecting amyloidosis. Herein, the transformation of ZnO NPs and adamantane-1-carboxylic acid (ADA) to advanced pH responsive nanosystems is reported. Primary ZnO NPs were isolated under a simple solvothermal self-assembly synthetic procedure in the sole presence of octadecylamine (ODA). By adjusting the reaction time (8–24 h), wurtzites of crystallite sizes 19, 21 and 23 nm, respectively, were synthesized with co-crystallized ODA in monoloayer or bilayer conformation. The NPs with the bilayer of ODA have been functionalized with ADA through an amide bond, while those with the ODA monolayer were further PEGylated and ADA was loaded. Loaded ADA-ZnO nanosystems affected insulin amyloidosis in acidic pH (4.8), both in terms of final aggregation status (40 %) and by retarding the lag phase of amyloids formation. The sustained release profile of ADA was confirmed, while interaction with calf thymus DNA (CT-DNA) was evidenced by hyperchromicity. The pH of 4.8 was not enough to cleave the peptide bond, and thus the direct conjugation of ADA was effective only in prolonging the lag phase, without affecting the final amyloid formation, giving rise to the inherent properties of ZnO, foregrounding a prodrug character.

PH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O2−.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2−. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO−.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.

Responsive nanosystems for targeted therapy of ulcerative colitis: Current practices and future perspectives

The pharmacological approach to treating gastrointestinal diseases is suffering from various challenges. Among such gastrointestinal diseases, ulcerative colitis manifests inflammation at the colon site specifically. Patients suffering from ulcerative colitis notably exhibit thin mucus layers that offer increased permeability for the attacking pathogens. In the majority of ulcerative colitis patients, the conventional treatment options fail in controlling the symptoms of the disease leading to distressing effects on the quality of life. Such a scenario is due to the failure of conventional therapies to target the loaded moiety into specific diseased sites in the colon. Targeted carriers are needed to address this issue and enhance the drug effects. Conventional nanocarriers are mostly readily cleared and have nonspecific targeting. To accumulate the desired concentration of the therapeutic candidates at the inflamed area of the colon, smart nanomaterials with responsive nature have been explored recently that include pH responsive, reactive oxygen species responsive (ROS), enzyme responsive and thermo – responsive smart nanocarrier systems. The formulation of such responsive smart nanocarriers from nanotechnology scaffolds has resulted in the selective release of therapeutic drugs, avoiding systemic absorption and limiting the undesired delivery of targeting drugs into healthy tissues. Recent advancements in the field of responsive nanocarrier systems have resulted in the fabrication of multi-responsive systems i.e. dual responsive nanocarriers and derivitization that has increased the biological tissues and smart nanocarrier’s interaction. In addition, it has also led to efficient targeting and significant cellular uptake of the therapeutic moieties. Herein, we have highlighted the latest status of the responsive nanocarrier drug delivery system, its applications for on–demand delivery of drug candidates for ulcerative colitis, and the prospects are underpinned.

Metal phenolic networks (MPNs)-based pH-sensitive stimulus responsive nanosystems for drug delivery in tumor microenvironment

The tumor microenvironment (TME) is a dynamic and complex system characterized by different cellular, molecular, and physiological heterogeneity. Therefore, conventional drug delivery strategies often failed to deliver an effective dosage to kill cancerous cells. In recent years, the development of nano-based drug delivery has expanded into a wide range of clinical applications to address the limitations of free therapeutics and voyage the biological barriers. Recently, stimuli-responsive metal phenolic networks (MPNs) have recently become a focus of intense scientific investigation in biomedical applications, and offer a versatile platform for controlled release of therapeutics in TME. This review provides a timely and thorough description of the use of a MPNs in the rapidly evolving field of advanced drug delivery with insights unique to pH-stimulus responsive systems. This review aims to offer an in-depth understanding of the potential use of MPNs as pH-sensitive therapeutics carriers in TME. We briefly explained the endogenous pH-associated factors affecting the therapeutics delivery in TME. A cross comparison of the advantages and disadvantages of MPNs with other counterparts are highlighted to elucidate their key design principles for pH-stimulus responsive drug delivery in TME. In later sections, pros and cons of MPNs as well as current challenges and future perspectives are also discussed, which will deepen our understanding of designing, fabricating, and applying MPNs for advanced therapeutics.

Tumor microenvironment-responsive nanosystem achieves reactive oxygen species self-cycling after photothermal induction to enhance efficacy of antitumor therapy

Tumor microenvironment response and spatio-temporal targeting are promising strategies to combination therapy. By regulating the tumor microenvironment and realizing the precise targeted therapy, the antitumor efficacy can be significantly improved while maintaining low side effects. Therefore, in this study, a reactive oxygen species (ROS)-responsive nanosystem (MND-IR@RESV) was constructed. The MND-IR@RESV nanosystem could be accurately tracked and located due to its own fluorescence. Mitochondria-targeted nanosystem promoted the release of ROS and contributed to the apoptosis of cancer cells. The MND-IR@RESV responded significantly to ROS, which promoted the deep release of drugs. Furthermore, the system also possessed high photothermal conversion efficiency and photothermal stability, which could achieve spatio-temporal targeting of drugs and ensure the efficient tumor eradication ability of Chemo/Photothermal/Photodynamic (CT-PTT-PDT) combination therapy. Both in vitro and in vivo tests demonstrated the significant antitumor effect of the MND-IR@RESV. Importantly, the nanosystem had the advantages of low toxicity and few side effects that conventional CT lacks, indicating that the MND-IR@RESV holds great promise in future cancer treatment.

Nanozyme-like single-atom catalyst combined with artesunate achieves photothermal-enhanced nanocatalytic therapy in the near-infrared biowindow.

Selectively generating active free radical (AFR) in tumor microenvironment (TME) can promote irreversible oxidation of biomolecules and damage tumor cells, resulting in effective tumor inhibition. However, therapeutic efficacy of AFR-based tumor suppression approaches is often limited by insufficient amount of H2O2 or O2 within TME. To overcome this obstacle, we design a pH/photothermal dual responsive nanosystem (PFeSA@AS) for combined photothermal and nanocatalytic therapy in the near-infrared biowindow. Here the Fe single-atom dispersed N, S-doped carbon nanosheets (FeSA) nanozyme is dispersed by phospholipid-polyethylene glycol-amine (DSPE-PEG-NH2), and further loads artesunate (AS) via an amide reaction. Upon 808-nm laser irradiation in TME, the AS is released and further be catalyzed by the FeSA nanozyme to produce cytotoxic C-centered AFRs, and further be accelerated due to the photothermal conversion performance of FeSA (23.35%). The nanocatalytic process of FeSA nanozyme is realized by density functional theory (DFT). The tumor inhibition rates of a CT26 xenograft model is 92% through a photothermal-enhanced nanocatalytic synergistic therapy, and negligible systematic toxicity is observed. This work offers a potential paradigm of multifunctional single atomic catalysts (SACs) for enhancing tumor nanocatalytic therapy. STATEMENT OF SIGNIFICANCE: We designed a pH/photothermal dual responsive nanosystem (PFeSA@AS) for nanocatalytic therapy: (1) the nanosystem responsively releases AS under 808-nm laser irradiation in TME; (2) FeSA in the nanosystem can act as heme mimetic to convert AS into high cytotoxic C-centered free radicals for nanocatalytic therapy; (3) the photothermal conversion performance of FeSA further enhances the catalytic process to yield abundant AFR. Both in vitro and in vivo results demonstrate that this nanosystem can efficiently inhibit tumor growth through a photothermal-enhanced nanocatalytic synergistic therapy.

Tumor-Specific NIR-Activatable Nanoreactor for Self-Enhanced Multimodal Imaging and Cancer Phototherapy.

Responsive nanosystems for tumor treatment with high specificity and sensitivity have aroused great attention. Herein, we develop a tumor microenvironment responsive and near-infrared (NIR)-activatable theranostic nanoreactor for imaging-guided anticancer therapy. The nanoreactor (SnO2-x@AGP) is comprised of poly(vinylpyrrolidine) encapsulated hollow mesoporous black SnO2-x nanoparticles coloaded with glucose oxidase (GOx) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The constructed nanoreactor can be specifically activated through endogenous H2O2 by an NIR-mediated "bursting-like" process to enhance its imaging and therapeutic functions. Black SnO2-x with abundant oxygen vacancies expedites effective separation of electron-hole pairs from energy-band structure and endows them with strong hyperthermia effect upon NIR laser irradiation. The generating toxic H2O2 with the assistance of GOx provides SnO2-x@AGP with the capacity of oxidative stress therapy. Ascended H2O2 can activate ABTS into ABTS•+. ABTS•+ not only possesses significant NIR absorption properties, but also disrupts intracellular glutathione to generate excessive reactive oxygen species for improved phototherapy, leading to more effective treatment together with oxidative stress therapy. Thus, SnO2-x@AGP with NIR-mediated and H2O2-activated performance presents tumor inhibition efficacy with minimized damage to normal tissues. These outstanding characteristics of SnO2-x@AGP bring an insight into the development of activatable nanoreactors for smart, precise, and non-invasive cancer theranostics.

Biomarker‐Responsive Nanosystems for Chronic Disease Theranostics

AbstractChronic diseases claim millions of lives every year, and it is of great significance to explore and develop advanced drugs to improve the cure rate of chronic diseases. Nanotheranostics are innovative strategies that enable the integration of diagnostic and therapeutic properties into a single nanosystem. Despite great success in nanotheranostics, their applications of nanotheranostics in nanomedicine are still in their infancy. This is because each disease has its corresponding characteristic pathological microenvironment, which motivates the development of endogenous biomarker‐responsive nanosystems to meet the requirements of diagnosis and treatment. Herein, recent progress is presented in biomarker‐responsive nanosystems and their biomedical applications. First, biomarker‐responsive nanosystems are classified into eight subsections according to the type of chronic diseases, including tumors, cardiovascular diseases, neurological diseases, Wilson's diseases, chronic liver diseases, chronic kidney diseases, diabetes mellitus, and rheumatoid arthritis. In the following, a variety of intriguing applications of biomarkers‐responsive nanosystems are briefly elaborated, such as biosensing, diagnosis, therapy, combined theranostics, and early evaluation of therapy effect, etc. Finally, the challenges and future directions from research to clinical translation of these responsive nanosystems are also presented.

NIR-II Responsive Molybdenum Dioxide Nanosystem Manipulating Cellular Immunogenicity for Enhanced Tumor Photoimmunotherapy.

Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.

Exploring magneto-electric nanoparticles (MENPs): a platform for implanted deep brain stimulation

Exploring magneto-electric nanoparticles (MENPs): a platform for implanted deep brain stimulation

Hemithioindigo-Based Trioxobicyclononadiene: 3D Multiswitching of Electronic and Geometric Properties.

Molecular photoswitches that offer simultaneous precise control over geometrical and electronic changes are rare yet highly sought tools for the development of responsive nanosystems. Here we present such an advantageous combination of property control within a novel multiphotoswitch architecture. Hemithioindigo-based trioxobicyclononadiene (HTI-TOND) offers a rigid three-dimensional molecular structure that undergoes different exotic rearrangement reactions upon photochemical and thermal signaling. Three to four different states with distinct geometric and electronic properties can be accessed reversibly in high yields within this molecular framework. Thus, a highly promising and unique switching tool has become available to instill the next level of addressability at the smallest scales.

Self-Assembled Fluorosome-Polydopamine Complex for Efficient Tumor Targeting and Commingled Photodynamic/Photothermal Therapy of Triple-Negative Breast Cancer.

Photodynamic/photothermal therapy (PDT/PTT) that deploys a near-infrared responsive nanosystem is emerging to be a promising modality in cancer treatment. It is highly desirable to have a multifunctional nanosystem that can be used for efficient tumor targeting and inhibiting metastasis/recurrence of cancer. In the current study, self-assembled chlorophyll-rich fluorosomes derived from Spinacia oleracea were developed. These fluorosomes were co-assembled on a polydopamine core, forming camouflaged nanoparticles (SPoD NPs). The SPoD NPs exhibited a commingled PDT/PTT (i.e., interdependent PTT and PDT) that inhibited both normoxic and hypoxic cancer cell growth. These nanoparticles showed stealth properties with enhanced physiological stability and passive tumor targeting. SPoD NPs also exhibited tumor suppression by synergistic PTT and PDT. It also prevented lung metastasis and splenomegaly in tumor-bearing Balb/c mice. Interestingly, treatment with SPoD NPs also caused the suppression of secondary tumors by eliciting an anti-tumor immune response. In conclusion, a co-assembled multifunctional nanosystem derived from S. oleracea showed enhanced stability and tumor-targeting efficacy, resulting in a commingled PDT/PTT effect.

Biologically Responsive Nanosystems Targeting Cardiovascular Diseases.

Cardiovascular Diseases (CVD) remain the leading cause of mortality and morbidity worldwide. To date, significant progress has been made in developing stimuli-responsive nanosystems that can intrinsically interact with pathological microenvironment to achieve site-specific delivery along with on-demand drug release for precise CVD treatment. Herein, this review summarizes recent advances on smart nanosystems in response to a wide range of biological cues, including pH, enzymes, ROS, shear force, ATP, etc., which can boost drug delivery performance or monitor disease progression in a non-invasive manner. The designs, compositions and main outcomes of the single and multi-responsive nanosystems for drug delivery and/or detection purposes are provided and discussed.

A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer.

Rationale: The synergism of new modalities alongside chemodynamic therapy into common chemotherapy has shown promising potential in clinical applications. This paper reports a tumor microenvironment-responsive nanosystem for chemodynamic/chemical synergistic therapy and magnetic resonance imaging (MRI).Methods: The biodegradable nanosystem is synthesized using a surface-modified chain transfer agent for surface-initiated living radical polymerization of the chemotherapeutic drug.Results: In this nanosystem, named CAMNSN@PSN38, the cycling time and solubility of the chemotherapeutic drug are improved. The nanoparticles delivered to tumor tissues gradually release the chemotherapeutic drug and Mn2+ through glutathione (GSH)-triggered biodegradation in the tumor microenvironment. SN38, the released chemotherapeutic drug, not only shows excellent chemical therapy effects but also improves the generation of H2O2. Furthermore, with the Fenton-like agent Mn2+, the generation of reactive oxygen species (ROS) is improved markedly. Finally, CAMNSN@PSN38 shows excellent inhibition of tumor growth in three colorectal cancer tumor models, with an improved accumulation of ROS and controlled release of SN38.Conclusions: The CAMNSN@PSN38-mediated chemodynamic/chemical synergistic therapy provides a promising paradigm for the treatment and MRI-guided therapy of colorectal cancer.

Hydrophilic polymer driven crystallization self-assembly: an inflammatory multi-drug combination nanosystem against Alzheimer's disease.

The hydrophobic polymer driven crystallization of self-assembled micelles is usually sufficient for their purposes in materials chemistry studies. However, with the state of smart drug delivery research, micelles alone are not enough. The principles of the self assembly driven by hydrophilic dextran brushes together with charged poly(3-acrylamidophenyl boronic acid) (PPBA) are uncovered in this study. A series of poly(ε-caprolactone)-block-poly(3-acrylamidophenyl boronic acid)-dextran (PCL-b-PPBA-Dex) micelles and vesicles are investigated as potential Alzheimer's disease (AD) treatments. Three inflammatory microenvironment responsive micelles, including celecoxib drug-loaded micelles (CEL), ibuprofen drug-loaded micelles (IBU) and telmisartan drug-loaded micelles (TEL), are developed. In vivo, CEL/IBU (mixture of CEL and IBU) and CEL/TEL (mixture of CEL and TEL) suppress the activation of glia and reduce the levels of inflammatory mediators through eliminating cyclooxygenase 2 (COX-2) signals. The CEL/TEL combination nanosystem is better at correcting neuroinflammation and improving the spatial memory ability of a senescence-accelerated mouse prone 8 model (SAMP8). We consider that the inflammation responsive combination nanosystem provides a new potential treatment for AD clinical patients.