Hybrid Hydrogel-Magnet Actuators with pH-Responsive Hydrogels for Gastrointestinal Microrobots

Limited space on millimeter-scale devices for biomedical applications makes it challenging to incorporate bulky actuators and power for onboard mechanical actuation. Stimuli-responsive hydrogels, such as pH-responsive hydrogels, provide a solution to automatically sense and actuate in the gastrointestinal tract. However, hydrogels are often nonload bearing and slow in actuation. To overcome these challenges, a new type of hybrid actuator is developed which utilizes a pH-responsive hydrogel with magnets to trigger magnetic springs (i.e., permanent magnets with repulsive, spring-like forces) to quickly initiate rotational and translational movements at pH > 6. The agar-poly(acrylic acid) hydrogel undergoes a large volume transition at pH > 6 and exhibits large nominal blocking stress of 610–819 kPa for a 3–4 mm diameter cylinder hydrogel. Moreover, the scaling of hydrogel force and response times are experimentally confirmed. Based on the hydrogel properties, an analytical hydrogel model is developed to predict hydrogel force and displacement under varying magnetic loads and wall constraints in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 6.8), and the experimental data validate the model. Finally, an innovative hybrid hydrogel-magnet actuator that triggers rotational and translational motion without external activation is demonstrated.     

超疏水耐水洗的pH响应性聚苯胺变色织物

采用一种表面存在大量微/纳米裂纹、 横截面为十字型异型纤维的涤棉混纺织物作为基底, 以全氟壬烯氧基苯磺酸钠(OBS)作为掺杂剂, FeCl₃为氧化剂, 通过原位化学氧化法制备得到了具有超疏水性能和耐水洗的聚苯胺/涤棉复合导电织物(PANI/CPCCT), 研究了pH对PANI/CPCCT的影响。结果表明, 该导电织物的水接触角最高可达162°, 在碱性条件下仍具有良好的导电性能和疏水性, 并且其颜色也随着pH从1增大至14而发生由墨绿色-蓝绿色-蓝黑色-褐色之间的可逆变化, 其浸润性可快速响应外界酸度的变化, 发生超疏水到超亲水的可逆转变, 具有良好的pH响应性。此外, PANI/CPCCT可耐受弱酸性溶液的洗涤, 并可通过在强酸溶液中浸泡而重复使用, 具有较强的应用性。这些优良的性能, 使其有望在开发酸度控制的浸润性开关、 自清洁织物、 酸度检测等方面获得应用。     

On-Demand Removable Self-Healing and pH-Responsive Europium-Releasing Adhesive Dressing Enables Inflammatory Microenvironment Modulation and Angiogenesis for Diabetic Wound Healing

Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self-healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin–europium coordination complex crosslinked citrate-based mussel-inspired bioadhesives (TE-CMBAs) are specially developed for diabetic wound healing. TE-CMBAs can gel instantly (< 60 s), possess favorable shape-adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti-oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal–phenolic coordination also confers TE-CMBAs with self-healability, pH-responsive europium ion and TA releasing properties and on-demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.     

A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells

Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.     

Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo

Mitochondria‐mediated apoptosis (MMA) is a preferential option for cancer therapy due to the presence of cell‐suicide factors in mitochondria, however, low permeability of mitochondria is a bottleneck for targeting drug delivery. In this paper, glycyrrhetinic acid (GA), a natural product from Glycyrrhiza glabra, is found to be a novel mitochondria targeting ligand, which can improve mitochondrial permeability and enhance the drug uptake of mitochondria. GA‐functionalized graphene oxide (GO) is prepared and used as an effective carrier for targeted delivery of doxorubicin into mitochondria. The detailed in vitro and in vivo mechanism study shows that GA‐functionalized GO causes a decrease in mitochondrial membrane potential and activates the MMA pathway. The GA‐functionalized drug delivery system demonstrates highly improved apoptosis induction ability and anticancer efficacy compared to the non‐GA‐functionalized nanocarrier delivery system. The GA‐functionalized nanocarrier also shows low toxicity, suggesting that it can be a useful tool for drug delivery.     

pH值响应性透明质酸纳米粒的制备及作为阿霉素载体的研究

通过化学交联法合成组氨酸修饰透明质酸耦合物(His-HA),制备载阿霉素纳米粒,分析其pH值响应性和抗肿瘤特征.研究显示,随着pH值的降低(7.4～5.5),纳米粒的粒径增大(230～780nm),zeta电位升高,载药纳米粒的体外释放量增加.细胞毒性实验显示粒径＜300nm的载药纳米粒具更高的毒性.细胞摄入实验表明,阿霉素通过受体介导的胞吞和载药纳米粒的胞外释放两种途径被细胞摄入.以上研究显示组氨酸修饰透明质酸纳米粒具有显著的pH值响应性,具备作为阿霉素药物载体的应用前景.     

Smart Probe for Tracing Cancer Therapy: Selective Cancer Cell Detection,Image‐Guided Ablation,and Prediction of Therapeutic Response In Situ

Integrated diagnosis and therapy systems that can offer traceable cancer therapy are in high demand for personalized medicine. Herein, a pH‐responsive polymeric probe containing tetraphenylsilole (TPS) with aggregation‐induced emission characteristics and pheophorbide A (PheA) photosensitizer (PS) with aggregation‐caused quenching property for tracing the whole process of cancer therapy is reported. At physiological conditions (pH 7.4), the probe self‐assembles into nanoparticles (NPs), which show weak fluorescence of PheA with low phototoxicity, but strong green fluorescence from TPS for probe self‐tracking. Upon uptake by cancer cells and entrapment in lysosomes (pH 5.0), the NPs disassemble to yield weak emission of TPS but strong red fluorescence of PheA with restored phototoxicity for PS activation monitoring. Upon light irradiation, the generated reactive oxygen species can cause lysosomal disruption to trigger cell apoptosis. Meanwhile, the probe leaks to the cytoplasm (pH 7.2), where the TPS fluorescence is restored for in situ visualization of the therapeutic response. The probe design thus represents a novel strategy for traceable cancer therapy.     

A Novel Self‐Assembled Mitochondria‐Targeting Protein Nanoparticle Acting as Theranostic Platform for Cancer

Self‐assembled protein nanoparticles have attracted much attention in biomedicine because of their biocompatibility and biodegradability. Protein nanoparticles have become widely utilized as diagnostic or therapeutic agents for various cancers. However, there are no reports that protein nanoparticles can specifically target mitochondria. This targeting is desirable, since mitochondria are critical in the development of cancer cells. In this study, the discovery of a novel self‐assembled metal protein nanoparticle, designated GST‐MT‐3, is reported, which targets the mitochondria of cancer cells within 30 min in vitro and rapidly accumulates in tumors within 1 h in vivo. The nanoparticles chelate cobalt ions [GST‐MT‐3(Co²⁺)], which induces reactive oxygen species (ROS) production and reduces the mitochondrial membrane potential. These effects lead to antitumor activity in vivo. GST‐MT‐3(Co²⁺) with covalently conjugated paclitaxel synergistically suppress tumors and prolong survival. Importantly, the effective dosage of paclitaxel is 50‐fold lower than that utilized in standard chemotherapy (0.2 vs 10 mg kg^?1). To the best of the authors' knowledge, GST‐MT‐3 is the first reported protein nanoparticle that targets mitochondria. It has the potential to be an excellent platform for combination therapies.     

Mitochondria‐Targeting Magnetic Composite Nanoparticles for Enhanced Phototherapy of Cancer

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual‐modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria‐targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria‐targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.     

Dual Intratumoral Redox/Enzyme‐Responsive NO‐Releasing Nanomedicine for the Specific,High‐Efficacy,and Low‐Toxic Cancer Therapy

Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor‐targeted delivery and intratumoral stimuli‐responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor‐targeting and intratumoral microenvironment‐responsive NO‐releasing nanomedicines is highly desired. Here a novel kind of organic–inorganic composite nanomedicine (QM‐NPQ@PDHNs) is presented by encapsulating a glutathione S‐transferases π (GSTπ)‐responsive drug O²‐(2,4‐dinitro‐5‐{[2‐(β‐d ‐galactopyranosyl olean‐12‐en‐28‐oate‐3‐yl)‐oxy‐2‐oxoethyl] piperazine‐1‐yl} phenyl) 1‐(methylethanolamino)diazen‐1‐ium‐1,2‐dilate (NPQ) as NO donor and an aggregation‐induced‐emission (AIE) red fluorogen QM‐2 into the cores of the hybrid nanomicelles (PEGylated disulfide‐doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)‐responsive shells. The QM‐NPQ@PDHN nanomedicine is able to respond to the intratumoral over‐expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme‐responsive NO‐release nanomedicine for tumor‐specific and high‐efficacy cancer therapy.     

Enzyme-directed pH-responsive exfoliation and dispersion of graphene and its decoration by gold nanoparticles for use as a hybrid catalyst

A non-destructive, safe and practical strategy to produce high quality graphene in high yield is urgently required, since this would pave the way for a wide range of applications of graphene in the future. Here we present a pH-responsive water-dispersible method for the exfoliation and functionalization of graphene by using lysozyme. The pH-responsive dispersion of graphene may be useful for the reversible assembly of multicomponent/multifunctional nanohybrid materials and nanoscale electronic devices. More importantly, composites can be easily constructed through the interactions between disulphide groups in lysozyme and gold nanoparticles （AuNPs）. The resulting graphene-AuNPs composites show excellent catalytic activity towards reduction of o-nitroaniline by NaBH4. Since lysozyme is low cost and has antibacterial properties, and has been widely used in food preservation, medicine and the pharmaceutical industry, our approach may open a new scalable route for the manufacture of high-quality, nondestructive graphene for practical applications.     

Multifunctional Au@mSiO2/Rhodamine B Isothiocyanate Nanocomposites: Cell Imaging,Photocontrolled Drug Release,and Photothermal Therapy for Cancer Cells

The synthesis of Au@mesoporous SiO₂/rhodamine B isothiocyanate (Au@mSiO₂/RBITC) composite nanoparticles (NPs) is presented and their unique biofunctional properties are studied. The structure and morphology of the NPs are characterized by X‐ray powder diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. These NPs can not only be functionalized for fluorescence imaging, but also possess well‐defined mesopore structures for drug loading and strong infrared surface plasmon absorption for light‐controlled drug release and photothermal therapy for cancer cells. In the biological experiments, one 808 nm laser is coupled to a confocal laser scanning microscopy (CLSM) system to monitor the photothermal therapy, drug release, and cell position and viability in real time by using the multichannel function of CLSM for the first time. Such novel nanomaterials offer a new chemotherapeutic route for cancer treatment by combining cell imaging and hyperthermia in a synergistic way.     

A Peptide Nanofibrous Indicator for Eye‐Detectable Cancer Cell Identification

A unique peptide nanofibrous indicator (NFI) is fabricated by mixing a borono‐peptide with alizarin red S, followed by subsequent binding and self‐assembly. The NFI thus obtained exhibits an intense response to sialyl Lewis X tetrasaccharide, which is overexpressed in human hepatocellular carcinoma cell lines. Importantly, this NFI has the capability of specifically recognizing human hepatocellular liver carcinoma (HepG2) cells through the eye‐detectable color change resulting from strong binding‐induced displacement. This novel technique for cancer cell identification through direct unaided eye judgment will open up an innovative platform for cancer cell detection.     

Recent Advances in Cell Membrane–Camouflaged Nanoparticles for Cancer Phototherapy

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) employs phototherapeutic agents to generate heat or cytotoxic reactive oxygen species (ROS), and has therefore garnered particular interest for cancer therapy. However, the main challenges faced by conventional phototherapeutic agents include easy recognition by the immune system, rapid clearance from blood circulation, and low accumulation in target sites. Cell‐membrane coating has emerged as a potential way to overcome these limitations, owing to the abundant proteins on the surface of cell membranes that can be inherited to the cell membrane–camouflaged nanoparticles. This review summarizes the recent advances in the development of biomimetic cell membrane–camouflaged nanoparticles for cancer phototherapy. Different sources of cell membranes can be used to coat nanoparticles uisng different coating approaches. After cell‐membrane coating, the photophysical properties of the original phototherapeutic nanoparticles remain nearly unchanged; however, the coated nanoparticles are equipped with additional physiological features including immune escape, in vivo prolonged circulation time, or homologous targeting, depending on the cell sources. Moreover, the coated cell membrane can be ablated from phototherapeutic nanoparticles under laser irradiation, leading to drug release and thus synergetic therapy. By combining other supplementary agents to normalize tumor microenvironment, cell‐membrane coating can further enhance the therapeutic efficacy against cancer.     

Addressable Peptide Self‐Assembly on the Cancer Cell Membrane for Sensitizing Chemotherapy of Renal Cell Carcinoma

Chemotherapy has been validated unavailable for treatment of renal cell carcinoma (RCC) in clinic due to its intrinsic drug resistance. Sensitization of chemo‐drug response plays a crucial role in RCC treatment and increase of patient survival. Herein, a recognition‐reaction‐aggregation (RRA) cascaded strategy is utilized to in situ construct peptide‐based superstructures on the renal cancer cell membrane, enabling specifically perturbing the permeability of cell membranes and enhancing chemo‐drug sensitivity in vitro and in vivo. First, P1‐DBCO can specifically recognize renal cancer cells by targeting carbonic anhydrase IX. Subsequently, P2‐N₃ is introduced and efficiently reacts with P1‐DBCO to form a peptide P3, which exhibits enhanced hydrophobicity and simultaneously aggregates into a superstructure. Interestingly, the superstructure retains on the cell membrane and perturbs its integrity/permeability, allowing more doxorubicin (DOX) uptaken by renal cancer cells. Owing to this increased influx, the IC₅₀ is significantly reduced by nearly 3.5‐fold compared with that treated with free DOX. Finally, RRA strategy significantly inhibits the tumor growth of xenografted mice with a 3.2‐fold enhanced inhibition rate compared with that treated with free DOX. In summary, this newly developed RRA strategy will open a new avenue for chemically engineering cell membranes with diverse biomedical applications.     

Preparation and optimization of superabsorbent hydrogel micromatrices based on poly(acrylic acid), partly sodium salt-g-poly(ethylene oxide) for modified release of indomethacin

The purpose of this study was to prepare modified-release dosage of indomethacin (IND) in the form of micromatrices based on a superabsorbent hydrogel (SAH), poly(acrylic acid), partly sodium salt-g-poly(ethylene oxide) (PAAc-Na-g-PEO). A soaking procedure was used for the preparation of drug-loaded hydrogel micromatrices. The amount of IND, volume of drug-loading solution, and amount of PAAc-Na-g-PEO granules used for preparing micromatrices were the independent factors. The dependent factors were the measured responses from micromatrices, that is, percent recovery, percent entrapment efficiency, and the time at which 63.2% of the drug was released (T_d, minutes). A three-factor, three-level full factorial design (33) was created to optimize formulations. Nonlinear regression analysis indicated a good correlation between the measured responses and the independent factors. Optimum responses were obtained from medium levels of IND and SAH and low level of drug-loading solution. Differential scanning calorimetry, X-ray diffraction analysis, and scanning electron micrography indicated that IND crystals are physically adsorbed into the pores and irregular spaces of the hydrogel.