Stimuli-responsive Nanomaterials Research Articles

Scutellarin-loaded pH/H2O2 dual-responsive polymer cyclodextrin mesoporous silicon framework nanocarriers for enhanced cancer therapy

Stimulus-responsive nanomaterials, particularly with targeting capabilities, have garnered significant attention in the cancer therapy. However, the biological safety of these innovative materials in vivo remains unknown, posing a hurdle to their clinical application. Here, a pH/H2O2 dual-responsive and targeting nano carrier system (NCS) was developed using core shell structure of Fe3O4 mesoporous silicon (MSN@Fe3O4) as main body, scutellarin (SCU) as antitumor drug and polymer cyclodextrin (PCD) as molecular switch (denoted as PCD@SCU@MSN@Fe3O4, abbreviated as NCS). The NCS, with an average particle size of 100 nm, displayed exceptional SCU loading capacity, a result of its uniform radial channel structure. The in vitro investigation under condition of pH and H2O2 indicated that NCS performed excellent pH/H2O2-triggered SCU release behavior. The NCS displayed a higher cytotoxicity against tumor cells (Huh7 and HCT116) due to its pH/H2O2 dual-triggered responsiveness, while the PCD@MSN@Fe3O4 demonstrated lower cytotoxicity for both Huh7 and HCT116 cells. In vivo therapeutic evaluation of NCS indicates significant inhibition of tumor growth in mouse subcutaneous tumor models, with no apparent side-effects detected. The NCS not only enhances the bioavailability of SCU, but also utilizes magnetic targeting technology to deliver SCU accurately to tumor sites. These findings underscore the substantial clinical application potential of NCS.

Cuproptosis: Advances in Stimulus-Responsive Nanomaterials for Cancer Therapy.

Cuproptosis, a recently identified non-apoptotic programmed cell death modality, attracts considerable attention in the realm of cancer therapeutics owing to its unique cellular demise mechanisms. Since its initial report in 2022, strategies inducing or amplifying cuproptosis for cancer treatment emerge. The engineering of nano-systems to elicit cuproptosis effectively circumvents constraints associated with conventional small-molecule pharmaceutical interventions, presenting novel prospects for oncological therapy. Stimulus-responsive nanomaterials, leveraging their distinctive spatiotemporal control attributes, are investigated for their role in modulating the induction or augmentation of cuproptosis. In this comprehensive review, the physiological characteristics of cuproptosis, encompassing facets such as copper overload and depletion, coupled with regulatory factors intrinsic to cuproptosis, are expounded upon. Subsequently, design methodologies for stimulus-responsive induction or enhancement of cuproptosis, employing stimuli such as light, ultrasound, X-ray, and the tumor microenvironment, are systematically delineated. This review encompasses intricacies in nanomaterial design, insights into the therapeutic processes, and the associated advantages. Finally, challenges inherent in stimulus-responsive induction/enhancement of cuproptosis are deliberated upon and prospective insights into the future trajectory of copper-mediated cancer therapy are provided.

Direct Imaging of "Patch-Clasping" and Relaxation in Robust and Flexible Nanoparticle Assemblies.

Polymer patching on inorganic nanoparticles (NPs) enables multifunctionality and directed self-assembly into nonclosely packed optical and mechanical metamaterials. However, experimental demonstration of such assemblies has been scant due to challenges in leveraging patch-induced NP-NP attractions and understanding NP self-assembly dynamics. Here we use low-dose liquid-phase transmission electron microscopy to visualize the dynamic behaviors of tip-patched triangular nanoprisms upon patch-clasping, where polymer patches interpenetrate to form cohesive bonds that connect NPs. Notably, these bonds are longitudinally robust but rotationally flexible. Patch-clasping is found to allow highly selective tip-tip assembly, interconversion between dimeric bowtie and sawtooth configurations, and collective structural relaxation of NP networks. The integration of single particle tracking, polymer physics theory, and molecular dynamics simulation reveals the macromolecular origin of patch-clasping-induced NP dynamics. Our experiment-computation integration can aid the design of stimuli-responsive nanomaterials, such as topological metamaterials for chiral sensors, waveguides, and nanoantennas.

Release kinetics approach of stimuli-responsive mesoporous silica nanocarriers: pH-sensitive linker versus pH-sensitive framework

Silica-based stimuli-responsive nanomaterials have attracted significant attention in the field of drug delivery because they can achieve controlled release of anticancer drugs. For this, a gatekeeper is usually used, thus avoiding unwanted leakage at pH 7.4, while modulating the release under more acidic pH conditions in the tumor cell microenvironment. To optimize the efficiency of these nanostructures, it is crucial to study the release kinetics of anticancer drugs, predict their behavior, and modify the transport process mechanism. In the present study, we synthesized and characterized two types of pH-responsive mesoporous silica nanocarriers, which have transferrin conjugates on the surface serving as a gatekeeper. One nanocarrier was a conventional mesoporous silica nanoparticle (MSN) with transferrin attached through a pH-sensitive linker (MSN-Tf), while the other had a pH-sensitive diimine bridge in its framework, giving it degradable characteristic (dMSN-Tf). The use of conventional mathematical models and a three-parameter model that considers the drug-matrix interaction allowed the evaluation and elucidation of the different mechanisms involved in the kinetics of doxorubicin release from both materials at pH 7.4 and pH 5.0. The change in the kinetics of doxorubicin release from zero-order to first-order when it is in a degradable system such as dMSN-Tf, can be very useful for rapid drug delivery in acidic media such as inside cancer cells. Cell viability experiments in lung cancer cell lines A549 and H1299, showed enhanced anticancer activity by the nanomaterial with the pH-sensitive framework compared to the material that has a pH-sensitive linker. Overall, these findings provide important insights for optimizing the delivery of anticancer drugs.

Elucidation of Protonation Cooperativity of a STING-Activating Polymer.

Stimuli-responsive nanomaterials have the potential to improve the performance and overcome existing barriers of conventional nanotherapeutics. Molecular cooperativity design in stimuli-responsive nanomedicine can amplify physiological signals, enabling a cooperative response for improved diagnostic and therapeutic precision. Previously, this work reported an ultra-pH-sensitive polymer, PEG-b-PC7A, that possesses innate immune activating properties by binding to the stimulator of interferon genes (STING) through polyvalent phase condensation. This interaction enhances STING activation and synergizes with the endogenous STING ligand for robust cancer immunotherapy. Despite its successes in innate immune activation, the fundamental physicochemical and pH-responsive properties of PC7A require further investigation. Here, this study elucidates the protonation cooperativity driven by the phase transition of PC7A copolymer. The highly cooperative system displays an "all-or-nothing" proton distribution between highly charged unimer (all) and neutral micelle (nothing) states without gradually protonated intermediates. The binary protonation behavior is further illustrated in pH-precision-controlled release of a representative anticancer drug, β-lapachone, by PC7A micelles over a noncooperative PE5A polymer. Furthermore, the bimodal distribution of protons is represented by a high Hill coefficient (nH >9), featuring strong positive cooperativity. This study highlights the nanoscale pH cooperativity of an immune activating polymer, providing insights into the physicochemical characterization and design parameters for future nanotherapeutics development.

Stimuli-Responsive Nanoradiosensitizers for Enhanced Cancer Radiotherapy.

Radiotherapy (RT) has been a classical therapeutic method of cancer for several decades. It attracts tremendous attention for the precise and efficient treatment of local tumors with stimuli-responsive nanomaterials, which enhance RT. However, there are few systematic reviews summarizing the newly emerging stimuli-responsive mechanisms and strategies used for tumor radio-sensitization. Hence, this review provides a comprehensive overview of recently reported studies on stimuli-responsive nanomaterials for radio-sensitization. It includes four different approaches for sensitized RT, namely endogenous response, exogenous response, dual stimuli-response, and multi stimuli-response. Endogenous response involves various stimuli such as pH, hypoxia, GSH, and reactive oxygen species (ROS), and enzymes. On the other hand, exogenous response encompasses X-ray, light, and ultrasound. Dual stimuli-response combines pH/enzyme, pH/ultrasound, and ROS/light. Lastly, multi stimuli-response involves the combination of pH/ROS/GSH and X-ray/ROS/GSH. By elaborating on these responsive mechanisms and applying them to clinical RT diagnosis and treatment, these methods can enhance radiosensitive efficiency and minimize damage to surrounding normal tissues. Finally, this review discusses the additional challenges and perspectives related to stimuli-responsive nanomaterials for tumor radio-sensitization.

Precise antibacterial therapeutics based on stimuli-responsive nanomaterials.

Bacterial infection refers to the process in which bacteria invade, grow, reproduce, and interact with the body, ultimately causing a series of pathological changes. Nowadays, bacterial infection remains a significant public health issue, posing a huge threat to human health and a serious financial burden. In the post-antibiotic era, traditional antibiotics are prone to inducing bacterial resistance and difficulty in removing bacterial biofilm. In recent years, antibacterial therapy based on nanomaterials has developed rapidly. Compared with traditional antibiotics, nanomaterials effectively remove bacterial biofilms and rarely result in bacterial resistance. However, due to nanomaterials' strong permeability and effectiveness, they will easily cause cytotoxicity when they are not controlled. In addition, the antibacterial effect of non-responsive nanomaterials cannot be perfectly exerted since the drug release property or other antibacterial effects of these nano-materials are not be positively correlated with the intensity of bacterial infection. Stimuli-responsive antibacterial nanomaterials are a more advanced and intelligent class of nano drugs, which are controlled by exogenous stimuli and microenvironmental stimuli to change the dosage and intensity of treatment. The excellent spatiotemporal controllability enables stimuli-responsive nanomaterials to treat bacterial infections precisely. In this review, we first elaborate on the design principles of various stimuli-responsive antibacterial nanomaterials. Then, we analyze and summarizes the antibacterial properties, advantages and shortcomings of different applied anti-bacterial strategies based on stimuli-responsive nanomaterials. Finally, we propose the challenges of employing stimuli-responsive nanomaterials and corresponding potential solutions.

Preparation and characterization of nanocarriers based on polysaccharides from Lentinus edodes and bovine serum albumin and its photoprotection of resveratrol against UV radiation

In this work, biopolymer nanomaterials were prepared by electrostatic complexation and thermal treatment using the medicinal and edible homologous polysaccharides from Lentinus edodes (LEP) and bovine serum albumin (BSA). The hydrodynamic radius, PDI and zeta potential of the LEP-BSA nanocarriers (NCs) were 125.3 ± 1.2 nm, 0.206 ± 0.007 and − 25.3 ± 0.7 mV, respectively. SEM images of LEP-BSA NCs further demonstrated their uniform morphology. UV–vis, fluorescence and FTIR spectra revealed that LEP interacted successfully with BSA. And the presence of LEP caused the conformational change of BSA, which was confirmed by FTIR spectroscopy. The LEP-BSA NCs maintained good stability in long-term storage at different temperatures and kept integrity at neutral or slightly higher pH conditions. In vitro hemolysis and cytotoxicity experiments were performed to verify the biocompatibility of the LEP-BSA NCs. Furthermore, the ability of LEP-BSA NCs to encapsulate bioactive compounds was proved by the successful encapsulation of resveratrol and the photoprotection of resveratrol. This work will be applied to other polysaccharide-protein systems with unique activities to prepare multi-functional stimuli-responsive nanomaterials for better applications in food production and biopharmaceuticals.

Kinetics and Mechanism of Camptothecin Release from Transferrin-Gated Mesoporous Silica Nanoparticles through a pH-Responsive Surface Linker.

Stimuli-responsive nanomaterials have emerged as a promising strategy for inclusion in anticancer therapy. In particular, pH-responsive silica nanocarriers have been studied to provide controlled drug delivery in acidic tumor microenvironments. However, the intracellular microenvironment that the nanosystem must face has an impact on the anticancer effect; therefore, the design of the nanocarrier and the mechanisms that govern drug release play a crucial role in optimizing efficacy. Here, we synthesized and characterized mesoporous silica nanoparticles with transferrin conjugated on their surface via a pH-sensitive imine bond (MSN-Tf) to assess camptothecin (CPT) loading and release. The results showed that CPT-loaded MSN-Tf (MSN-Tf@CPT) had a size of ca. 90 nm, a zeta potential of -18.9 mV, and a loaded content of 13.4%. The release kinetic data best fit a first-order model, and the predominant mechanism was Fickian diffusion. Additionally, a three-parameter model demonstrated the drug-matrix interaction and impact of transferrin in controlling the release of CPT from the nanocarrier. Taken together, these results provide new insights into the behavior of a hydrophobic drug released from a pH-sensitive nanosystem.

Nano-mediated strategy for targeting and treatment of non-small cell lung cancer (NSCLC).

Lung cancer is the most common type of cancer, with over 2.1 million cases diagnosed annually worldwide. It has a high incidence and mortality rate, leading to extensive research into various treatment options, including the use of nanomaterial-based carriers for drug delivery. With regard to cancer treatment, the distinct biological and physico-chemical features of nano-structures have acquired considerable impetus as drug delivery system (DDS) for delivering medication combinations or combining diagnostics and targeted therapy. This review focuses on the use of nanomedicine-based drug delivery systems in the treatment of lung cancer, including the use of lipid, polymer, and carbon-based nanomaterials for traditional therapies such as chemotherapy, radiotherapy, and phototherapy. The review also discusses the potential of stimuli-responsive nanomaterials for drug delivery in lung cancer, and the limitations and opportunities for improving the design of nano-based materials for the treatment of non-small cell lung cancer (NSCLC).

Nanomaterials-mediated on-demand and precise antibacterial therapies

Bacterial infection is a series of pathological changes caused by bacteria invading the host and interacting with the body. Nowadays, bacterial infection remains a major public health issue and a severe threat to human life and health. Traditional antibiotic therapy is less effective against biofilms and easily causes bacterial resistance, which has urged the development of a substitute antibacterial strategy. Recently, antibacterial nanomaterials have attracted much attention. However, traditional nanomaterials face some problems of insufficient drug concentration at infectious sites and the toxicity of extravasated drug causes damage to healthy tissues. On the contrary, nanomaterials based on advanced on-demand and precise strategies reduce biological toxicity effectively while improving germicidal efficacy, since these type of nanodrugs have higher spatiotemporal controllability. Currently, some smart stimuli-responsive nanomaterials and targeting nanomaterials have been successfully constructed to achieve on-demand and precise antibacterial therapies. This review focuses on the mechanisms, working principles and antimicrobial properties of diverse nanoparticles based on on-demand and precise strategies. Meanwhile, the strengths and inferiorities of different on-demand and precise strategies have been discussed. Finally, this review concludes with our opinions on the future development directions for exploiting next-generation on-demand and precise antibacterial therapies.

Metal-organic framework decorated with glycyrrhetinic acid conjugated chitosan as a pH-responsive nanocarrier for targeted drug delivery

Stimulus-responsive nanomaterials have become a hot spot in controllable drug delivery systems researches owing to their spatiotemporal controllable properties based on the differences between tumor microenvironment and normal tissue. Herein, iron (III) carboxylate metal-organic framework nanoparticles coated with glycyrrhetinic acid-chitosan conjugate (MIL-101/GA-CS) were successfully fabricated and acted as the pH-responsive and target-selective system to deliver doxorubicin (DOX) for hepatocellular carcinoma (HCC) therapy. The prepared nanocarrier possess the advantages of uniform size, comparable drug loading efficiency (28.89%), and superior pH-dependent controlled drug release (DOX release of 2.74% and 89.18% within 72 h at pH 7.4 and 5.5, respectively). In vitro cytotoxicity assays showed that the drug-loaded nanocarriers exhibited excellent inhibitory effects on HepG2 cells due to the sustained release of DOX, while the nanocarriers showed no significant toxicity. Furthermore, cell uptake experiments demonstrated that MIL-101-DOX/GA-CS could target HepG2 cells based on receptor-dependent internalization of glycyrrhetinic acid receptors mediated. In vitro 3D hepatoma cell microspheres experiments showed that MIL-101-DOX/GA-CS had excellent penetration and tumor killing ability. Therefore, MIL-101-DOX/GA-CS nanoparticles have a prospective application in cancer therapy as a pH-responsive controlled drug delivery system.

Designing supramolecular self-assembly nanomaterials as stimuli-responsive drug delivery platforms for cancer therapy.

Stimuli-responsive nanomaterials have attracted substantial interest in cancer therapy, as they hold promise to deliver anticancer agents to tumor sites in a precise and on-demand manner. Interestingly, supramolecular chemistry is a burgeoning discipline that entails the reversible bonding between components at the molecular and nanoscale levels, and the recent advances in this area offer the possibility to design nanotherapeutics with improved controllability and functionality for cancer therapy. Herein, we provide a comprehensive summary of typical non-covalent interaction modes, which primarily include hydrophobic interaction, hydrogel bonding, host-guest interaction, π-π stacking, and electrostatic interaction. Special emphasis is placed on the implications of these interaction modes to design novel stimuli-responsive drug delivery principles and concepts, aiming to enhance the spatial, temporal, and dosage precision of drug delivery to cancer cells. Finally, future perspectives are discussed to highlight current challenges and future opportunities in self-assembly-based stimuli-responsive drug delivery nanotechnologies for cancer therapy.

Stimuli responsive hierarchical assembly of supramolecular conductive fibers from coiled-coil building blocks.

Proteins and peptides provide inspiration for synthetic stimuli-responsive nanomaterials. In this work, the assembly mechanism of a de novo designed peptide that forms α-helical coiled-coil hexamer fibers was probed through point mutations of the amino acid sequence and varying assembly solution pH. Buffer pH affects multi-scale aspects of supramolecular assembly, including peptide monomer secondary structure and interactions between α-helical coiled-coil hexamer building blocks. These higher order assembly interfaces are formed by electrostatic networks between solvent-exposed polarizable side chains, as observed by cryo-electron microscopy. One of the resulting hierarchical structures was a novel assembly of α-helical cross coiled-coils that exhibits electrical conductivity. Here, we show that pH-gated assembly can be achieved with only one amino acid mutation. This work opens materials design for more stimuli-responsive and functional materials with simple pH-gating structural motifs.

Ferroptosis: challenges and opportunities for nanomaterials in cancer therapy.

Ferroptosis, a completely new form of regulated cell death, is mainly caused by an imbalance between oxidative damage and reductive protection and has shown great anti-cancer potential. However, existing small-molecule ferroptosis inducers have various limitations, such as poor water solubility, drug resistance and low targeting ability, hindering their clinical applications. Nanotechnology provides new opportunities for ferroptosis-driven tumor therapy. Especially, stimuli-responsive nanomaterials stand out among others and have been widely researched because of their unique spatiotemporal control advantages. Therefore, it's necessary to summarize the application of those stimuli-responsive nanomaterials in ferroptosis. Here, we describe the physiological feature of ferroptosis and illustrate the current challenges to induce ferroptosis for cancer therapy. Then, nanomaterials that induce ferroptosis are classified and elaborated according to the external and internal stimuli. Finally, the future perspectives in the field are proposed. We hope this review facilitates paving the way for the design of intelligent nano-ferroptosis inducers.

Molecularly Imprinted Nanomaterials with Stimuli Responsiveness for Applications in Biomedicine.

The review aims to summarize recent reports of stimuli-responsive nanomaterials based on molecularly imprinted polymers (MIPs) and discuss their applications in biomedicine. In the past few decades, MIPs have been proven to show widespread applications as new molecular recognition materials. The development of stimuli-responsive nanomaterials has successfully endowed MIPs with not only affinity properties comparable to those of natural antibodies but also the ability to respond to external stimuli (stimuli-responsive MIPs). In this review, we will discuss the synthesis of MIPs, the classification of stimuli-responsive MIP nanomaterials (MIP-NMs), their dynamic mechanisms, and their applications in biomedicine, including bioanalysis and diagnosis, biological imaging, drug delivery, disease intervention, and others. This review mainly focuses on studies of smart MIP-NMs with biomedical perspectives after 2015. We believe that this review will be helpful for the further exploration of stimuli-responsive MIP-NMs and contribute to expanding their practical applications especially in biomedicine in the near future.

Unexpected enhancement of pH-stability in Au3+/Ag+ loaded H-bonded layer-by-layer thin films.

In this work, a polymeric film was synthesized through a layer-by-layer (LBL) self-assembly technique using polyacrylic acid (PAA) and polyethylene oxide (PEO), resulting in the formation of a hydrogen-bonded LBL film. The formation of these films was evaluated by PMIRRAS and QCM-D. The synergy of these techniques allowed the understanding of the mechanism of formation of the film by showing the H-bonding formation and film growth. Au and Ag metal ions were successfully incorporated into the films, as corroborated by the combination of the information obtained by XRR and PMIRRAS. The films were exposed to increasing pH, showing a pronounced improvement in stability in films loaded with Au ions, extending the stability from pH 4 to 10. This behavior allows the use of this system in a wider range of applications, including the possibility of working in biological conditions. On the other hand, films loaded with Ag disintegrated at pH above 4. At acidic pH (below 3), these films released the Ag ions, which may be useful for the preparation of antibacterial stimuli-responsive nanomaterials. In both cases, the films were adequate to produce metal nanoparticles by metal loading and in situ reduction.

Carbon-Based Stimuli-Responsive Nanomaterials: Classification and Application.

Carbon-based nanomaterials, including carbon nanotubes, carbon nanospheres, and carbon nanofibers, are becoming a research hotspot due to their unique structure and good mechanical, thermal, electrical, optical, and chemical properties. With the development of material synthesis technology, they can be functionalized and used in various fields such as energy, environment, and biomedicine. In particular, stimuli-responsive carbon-based nanomaterials have stood out in recent years because of their smart behavior. Researchers have applied carbon-based nanomaterials to different disease treatments based on their stimulus-response properties. In this paper, based on stimuli-responsive carbon-based nanomaterials' morphology, we categorize them into carbon nanotubes, carbon nanospheres, and carbon nanofibers according to their morphology. Then, their applications in probes, bioimaging, tumor therapy, and other fields are discussed. Finally, we address the advantages and disadvantages of carbon-based stimuli-responsive nanomaterials and discuss their future perspective.

Hypoxia-responsive nanomaterials for tumor imaging and therapy.

Hypoxia is an important component of tumor microenvironment and plays a pivotal role in cancer progression. With the distinctive physiochemical properties and biological effects, various nanoparticles targeting hypoxia had raised great interest in cancer imaging, drug delivery, and gene therapy during the last decade. In the current review, we provided a comprehensive view on the latest progress of novel stimuli-responsive nanomaterials targeting hypoxia-tumor microenvironment (TME), and their applications in cancer diagnosis and therapy. Future prospect and challenges of nanomaterials are also discussed.

Recent Advances in Nanotheranostic Agents for Tumor Microenvironment-Responsive Magnetic Resonance Imaging.

Nanomaterials integrating a variety of excellent properties (such as controllable/suitable size, surface modifier, and multifunctionality) have attracted increasing attention in the biomedical field and have been considered a new generation of magnetic resonance imaging (MRI) contrast agents (CAs). In recent years, stimuli-responsive nanomaterials with specifically responsive ability have been synthesized as MRI CAs, which can significantly improve the diagnostic sensitivity and accuracy depending on their outstanding performance. Furthermore, the inherent tumor microenvironment (TME) of malignant tumor is considered to possess several unique features, such as low extracellular pH, redox condition, hypoxia, and high interstitial pressure, that are significantly different from healthy tissues. Hence, constructing nanomaterials for TME-responsive MRI as an emerging strategy is expected to overcome the current obstacles to precise diagnosis. This review focuses on recent advances of nanomaterials in their application of TME-responsive MRI that trigger the diagnostic function in response to various endogenous stimulations, including pH, redox, enzyme, and hypoxia. Moreover, the future challenges and trends in the development of nanomaterials serving as TME-responsive MRI CAs are discussed.