Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

pH‐Responsive Polymer–Drug Conjugate: An Effective Strategy to Combat the Antimicrobial Resistance

An urgent need for developing new antimicrobial approaches has emerged due to the imminent threat of antimicrobial‐resistant (AMR) pathogens. Bacterial infection can induce a unique microenvironment with low pH, which can be employed to trigger drug release and activation. Here, a pH‐responsive polymer–drug conjugate (PDC) capable of combating severe infectious diseases and overcoming AMR is reported. The PDC is made of a unique biodegradable and biocompatible cationic polymer Hex‐Cys‐DET and streptomycin, a model antibiotic. The two components show strong antimicrobial synergy since the polymer can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and bypassing the efflux pump. The PDC is neutralized for enhanced biocompatibility under physiological conditions but becomes positively charged while releasing the antibiotic in infected tissues due to the low pH. Additionally, the polymer contains disulfide bonds in its main chain, which makes it biodegradable in mammalian cells and thus reducing the cytotoxicity. The PDC can effectively penetrate bacterial biofilms and be taken up by mammalian cells, thereby minimizing biofilm‐induced AMR and intracellular infections. The PDC exhibits remarkable antimicrobial activity in three in vivo infection models, demonstrating its broad‐spectrum antimicrobial capability and great potency in eliminating AMR infections.     

Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.     

Tumor Intracellular‐Environment Responsive Materials Shielded Nano‐Complexes for Highly Efficient Light‐Triggered Gene Delivery without Cargo Gene Damage

Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochemical internalization (PCI) has provided the opportunity to overcome endo‐lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo‐oxidation of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light‐triggered gene delivery system is demonstrated based on endo‐lysosomal pH‐responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo‐lysosomal pH‐sensitive de‐shielding ability of the pH‐responsive shielding material incorporated in the ternary gene complexes (pH‐TCs), a more significant photo‐triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH‐insensitive material‐shielded nanocarriers cause photo‐oxidation of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light‐triggered gene delivery system using pH‐TCs is applied to deliver the therapeutic p53 gene in melanoma K‐1735 bearing mice, showing excellent therapeutic potential for cancer.     

Light‐Responsive,Singlet‐Oxygen‐Triggered On‐Demand Drug Release from Photosensitizer‐Doped Mesoporous Silica Nanorods for Cancer Combination Therapy

Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.     

Ag Nanoparticles Cluster with pH‐Triggered Reassembly in Targeting Antimicrobial Applications

Antibacterial efficiency can be effectively improved by applying targeting antibacterial materials and strategies. Herein, the successful synthesis of uniform pH‐responsive Ag nanoparticle clusters (AgNCs) is demonstrated, which can collapse and reassemble into nonuniform Ag NPs upon exposure to the acidic microenvironment of bacterial infections. This pH triggered reassembly contributes greatly to the improved antibacterial activities of AgNCs against both methicillin‐resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). The minimum inhibitory concentration and minimum bactericidal concentration against MRSA are as low as 4 and 32 µg mL^?1 (which are 8 and 32 µg mL^?1 for E. coli), respectively. In vivo skin wound healing experiments confirm AgNCs can serve as an effective wound dressing to accelerate the healing of MRSA infection. The development of responsive AgNCs offers new materials and strategies in targeting antibacterial applications.     

Biodegradable Nanoparticles of Polyacrylic Acid–Stabilized Amorphous CaCO3 for Tunable pH‐Responsive Drug Delivery and Enhanced Tumor Inhibition

Inorganic nanoparticles (NPs) are promising drug delivery carriers owing to their high drug loading efficiency, scalable preparation, facile functionalization, and chemical/thermal stability. However, the clinical translation of inorganic nanocarriers is often hindered by their poor biodegradability and lack of controlled pH response. Herein, a fully degradable and pH‐responsive DOX@ACC/PAA NP (pH 7.4–5.6) is developed by encapsulating doxorubicin (DOX) in poly(acrylic acid) (PAA) stabilized amorphous calcium carbonate (ACC) NPs. The DOX‐loaded NPs have small sizes (62 ± 10 nm), good serum stability, high drug encapsulation efficiency (>80%), and loading capacity (>9%). By doping proper amounts of Sr²⁺ or Mg²⁺, the drug release of NPs can be further modulated to higher pH responsive ranges (pH 7.7–6.0), which enables drug delivery to the specific cell domains of tissues with a less acidic microenvironment. Tumor inhibition and lower drug acute toxicity are further confirmed via intracellular uptake tests and zebrafish models, and the particles also improve pharmacokinetics and drug accumulation in mouse xenograft tumors, leading to enhanced suppression of tumor growth. Owing to the excellent biocompatibility, biodegradability, and tunable drug release behavior, the present hybrid nanocarrier may find broad applications in tumor therapy.     

pH‐Responsive Catalytic Janus Motors with Autonomous Navigation and Cargo‐Release Functions

The fabrication of multifunctional polymeric Janus colloids that display catalytically driven propulsion, change their size in response to local variations in pH, and vary cargo release rate is demonstrated. Systematic investigation of the colloidal trajectories reveals that in acidic environments the propulsion velocity reduces dramatically due to colloid swelling. This leads to a chemotaxis‐like accumulation for ensembles of these responsive particles in low‐pH regions. In synergy with this chemically defined accumulation, the colloids also show an enhancement in the release rate of an encapsulated cargo molecule. Together, these effects result in a strategy to harness catalytic propulsion for combined autonomous transport and cargo release directed by a chemical stimulus, displaying a greater than 30 times local cargo‐accumulation enhancement. Lactic acid can be used as the stimulus for this behavior, an acid produced by some tumors, suggesting possible eventual utility as a drug‐delivery method. Applications for microfluidic transport are also discussed.     

Activated Platelets‐Targeting Micelles with Controlled Drug Release for Effective Treatment of Primary and Metastatic Triple Negative Breast Cancer

The frequent relapse and metastasis characteristics of triple negative breast cancer (TNBC) make it a fraught issue with very poor prognosis in clinic. An effective treatment for TNBC should prevent and even eliminate metastasis as well as suppress primary lesion expansion. Recent progress reveals that platelets can be recruited and activated by tumor cells through intercellular adhesion molecules (ICAM), and help aggressive circulating tumor cells (CTCs) form metastasis. Therefore, activated platelets are considered with possession of tumor‐homing, CTC‐capturing, and metastasis‐targeting abilities. In this work, a P‐selectin (expressed on activated platelet surface) targeting peptide (PSN) is modified on a redox‐responsive paclitaxel‐loaded micelle (PSN‐PEG‐SS‐PTX₄ micelle) to utilize activated platelets as a “bridge” for interaction with cancer cells. The PSN‐modified micelle can easily adhere to the surface of activated platelets and subsequently capture CTCs in blood circulation. Compared to Taxol and PEG‐SS‐PTX₄ micelle, PSN‐PEG‐SS‐PTX₄ micelle also exhibits enhanced primary TNBC/metastasis targeting and penetrating effect through binding with tumor infiltrating platelets and thus significantly improves treatment outcome. More importantly, PSN‐PEG‐SS‐PTX₄ micelle potently suppressed lung metastasis of TNBC and reduced incidence of distant liver metastasis. The activated platelet‐targeting redox‐responsive micelle system provides a promising prospect for the omnidirectional treatment of metastatic cancer.     

A pH‐Responsive Gating Membrane System with Pumping Effects for Improved Controlled Release

In this study, we report on a novel composite membrane system for pH‐responsive controlled release, which is composed of a porous membrane with linear grafted, positively pH‐responsive polymeric gates acting as functional valves, and a crosslinked, negatively pH‐responsive hydrogel inside the reservoir working as a functional pumping element. The proposed system features a large responsive release rate that goes effectively beyond the limit of concentration‐driven diffusion due to the pumping effects of the negatively pH‐responsive hydrogel inside the reservoir. The pH‐responsive gating membranes were prepared by grafting poly(methacrylic acid) (PMAA) linear chains onto porous polyvinylidene fluoride (PVDF) membrane substrates using a plasma‐graft pore‐filling polymerization, and the crosslinked poly(N,N‐dimethylaminoethyl methacrylate) (PDM) hydrogels were synthesized by free radical polymerization. The volume phase‐transition characteristics of PMAA and PDM were opposite. The proposed system opens new doors for pH‐responsive “smart” or “intelligent” controlled‐release systems, which are highly attractive for drug‐delivery systems, chemical carriers, sensors, and so on.     

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t_1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg^?1; IR780, 0.8 mg kg^?1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.     

Smart Anisotropic Wetting Surfaces with Reversed pH‐Responsive Wetting Directions

Smart pH‐responsive surfaces that could autonomously induce unidirectional wetting of acid and base with reversed directions are fabricated. The smart surfaces, consisting of chemistry‐asymmetric “Janus” silicon cylinder arrays (Si‐CAs), are prepared by precise modification of functional groups on each cylinder unit. Herein, amino and carboxyl groups are chosen as typical pH‐responsive groups, owing to their protonation/deprotonation effect in response to pH of the contacted aqueous solution. One side of the Si‐CAs is modified by poly(2‐(dimethylamino)ethyl methacrylate), while the other side is modified by mixed self‐assembled monolayers of 1‐dodecanethiol and 11‐mercaptoundecanoic acid. On such surfaces, it is observed that acid and base wet in a unidirectional manner toward corresponding directions that are modified by amino or carboxyl groups, which is caused by asynchronous change of wetting property on two sides of the asymmetric structures. The as‐prepared Janus surfaces could regulate the wetting behavior of acid and base and could direct unidirectional wetting of water with reversed directions when the surfaces are treated by strong acid or base. Due to the excellent response capability, the smart surfaces are potential candidates to be applied in sensors, microfluidics, oil/water separation, and smart interfacial design.     

In Situ Generated Gold Nanoparticle Hybrid Polymersomes for Water‐Soluble Chemotherapeutics: Inhibited Leakage and pH‐Responsive Intracellular Release

Drug leakage in blood circulation is generally a serious concern to polymersomes when loading water‐soluble chemotherapeutics. If packing density of polymersome membrane is strengthened, premature drug release will be inhibited. Therefore, synthesis of a series of amphiphilic polyphosphazenes (PNPs) with 2‐diethylaminoethyl 4‐aminobenzoate (DEAB) as hydrophobic side groups and amino‐terminal poly(ethylene glycol) (NH₂‐PEG₂₀₀₀) as hydrophilic chains is presented. By controlling the ratio of DEAB to NH₂‐PEG₂₀₀₀, the optimal PNP‐3 is screened to ensure polymersome formation and high loading of doxorubicin hydrochloride (DOX·HCl). In situ generation method is initially employed to introduce gold nanoparticles (AuNPs) into vesicles' lamella, which can homogeneously distribute among DEAB sides via coordination interaction and act as inorganic cross‐linkers to aggregate polymer chains. Drug leakage of resultant AuNP hybrid PNP‐3 polymersome (IAuPNP‐3) at pH 7.4 is effectively alleviated and the systemic circulation time of DOX·HCl in mice is obviously prolonged. Besides, pH‐responsive drug release, due to the protonation of tertiary amine in DEAB, contributes to fast intracellular action. Based on the cooperation of these functions, DOX·HCl‐loaded IAuPNP‐3 finally achieves the highest in vivo antitumor efficacy compared with free DOX·HCl, drug‐loaded PNP, or EAuPNP prepared by prepreparation AuNPs method.     

Light‐Activatable Assembled Nanoparticles to Improve Tumor Penetration and Eradicate Metastasis in Triple Negative Breast Cancer

Triple‐negative breast cancer (TNBC) is a kind of aggressive malignancy with fast metastatic behavior. Herein, a nanosystem loaded with a near‐infrared (NIR) agent is developed to achieve chemo‐photothermal combination therapy for inhibiting tumor growth and metastasis in TNBC. The NIR agent of ultrasmall sized copper sulfide nanodots with strong NIR light‐absorbing capability is entrapped into the doxorubicin‐contained temperature‐sensitive polymer‐based nanosystem by a self‐assembled method. The temperature sensitive nanoclusters (TSNCs) can significantly enhance the drug penetration depth and significantly kill the cancer cells under the near‐infrared laser irradiation. Importantly, it is plausible that the tumor penetrating nanosystem combined with NIR laser irradiation can prevent lung and liver metastasis via extermination of the cancer stem cells. The in vivo characteristics, evaluated by photoacoustic imaging, pharmacokinetics, and biodistribution, confirm their feasibility for tumor treatment owing to their long blood circulation time and high tumor uptake. Thanks to the high tumor uptake and highly potent antitumor efficacy, the doxorubicin‐induced cardiotoxicity can be avoided when the TSNC is used. Taken together, it is believed that the nanosystem has excellent potential for clinical translation.     

Protein/Polymer‐Based Dual‐Responsive Gold Nanoparticles with pH‐Dependent Thermal Sensitivity

This article presents the synthesis and physicochemical behavior of dual‐responsive plasmonic nanoparticles with reversible optical properties based on protein‐coated gold nanoparticles grafted with thermosensitive polymer brushes by means of surface‐initiated atom transfer radical polymerization (SI‐ATRP) that exhibit pH‐dependent thermo‐responsive behavior. Spherical gold NPs of two different sizes (15 nm and 60 nm) and with different stabilizing agents (citrate and cetyltrimethylammonium bromide (CTAB), respectively) were first capped with bovine serum albumin (BSA). The resulting BSA‐capped NPs (Au@BSA NPs) exhibited not only extremely high colloidal stability under physiological conditions, but also a reversible U‐shaped pH‐responsive behavior, similar to pure BSA. The ?‐amine of the L‐lysine in the protein coating was then used to covalently bind an ATRP‐initiator, allowing for the SI‐ATRP of thermosensitive polymer brushes of oligo(ethylene glycol) methacrylates with an LCST of 42 °C in pure water and around 37 °C under physiological conditions. Such protein coated nanoparticles grafted with thermosensitive polymers exhibit a smart pH‐dependent thermosensitive behavior.     

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor‐specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)‐responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione‐activatable drugs, including dimer‐7‐ethyl‐10‐hydroxycamptothecin (d‐SN38) and dimer‐lonidamine (d‐LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d‐SN38 and d‐LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti‐PD‐L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli‐responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.     

Treatment of Malignant Brain Tumor by Tumor‐Triggered Programmed Wormlike Micelles with Precise Targeting and Deep Penetration

The efficient and specific drug delivery to brain tumor is a crucial challenge for successful systemic chemotherapy. To overcome these limitations, here a tumor‐triggered programmed wormlike micelle is reported with precise targeting and deep penetration to treat malignant gliomas, which is composed of pH‐responsive mPEG‐b‐PDPA copolymer and bioreducible cyclic RGD peptide targeted cytotoxic emtansine (DM1) conjugates (RGD‐DM1). The RGD‐DM1 loaded nanoscaled wormlike micelles (RNW) exhibit nanometer‐sized wormlike assemblies with the transverse diameter of 21.3±1.8 nm and length within 60–600 nm, and the RGD targeting peptide in RNW is 4.2% in weight. RNW can be dissociated at intracellular acidic environments to release RGD‐DM1, and be further degraded into DM1 by cleavage of disulfide bonds in the reductive milieu. In particular, by exploiting the unique wormlike structure and the RGD targeting peptide modification, RNW can be endowed with obviously enhanced drug delivery to brain, precise targeting to brain tumor, deep penetration into tumor mass, and efficient internalization into glioma cells in a programmed manner, thereby surprisingly leading to an 88.9% inhibition on tumor progression in an orthotopic brain tumor model. Therefore, the properly designed RNW can provide a promising delivery platform for systemic chemotherapy of brain tumor.     

NIR Light‐Triggered Degradable MoTe2 Nanosheets for Combined Photothermal and Chemotherapy of Cancer

Telluride molybdenum (MoTe₂) nanosheets with wide near‐infrared (NIR) absorbance are functionalized with polyethylene glycol‐cyclic arginine‐glycine‐aspartic acid tripeptide (PEG‐cRGD). After loading a chemotherapeutic drug (doxorubicin, DOX), MoTe₂‐PEG‐cRGD/DOX is used for combined photothermal therapy and chemotherapy. With the high photothermal conversion efficiency, MoTe₂‐PEG‐cRGD/DOX exhibits favorable cells killing ability under NIR irradiation. Owing to the cRGD‐mediated specific tumor targeting, MoTe₂‐PEG‐cRGD/DOX shows efficient accumulation in tumors to induce a strong tumor ablation effect. MoTe₂‐PEG‐cRGD nanosheets, which are relatively stable in the circulation, could be degraded under NIR ray. The in vitro and in vivo experimental results demonstrate that this theranostic nanoagent, which could accumulate in tumors to allow photothermal imaging and combined therapy, is readily degradable in normal organs to enable rapid excretion and avoid long‐term retention/toxicity, holding great potential to treat tumor effectively.