A Visible‐ and NIR‐Light Responsive Photothermal Therapy Agent by Chirality‐Dependent MoO3−x Nanoparticles

Chirality‐based semiconducting nanocrystals, as an emerging area, are envisioned to have great potential in chiral sensing, biomedicine, and chiroptical devices. Herein, chiral substoichiometric molybdenum oxide (l /d ‐Cys‐MoO_3?x) nanoparticles are synthesized via step‐by‐step reduction treatment with chiral cysteine molecules. The obtained nanoparticles are used as visible‐ and near‐infrared‐light dual responsive photothermal therapy agent for tumor cell ablation. Notably, the chiral nanoparticles show chiral selectivity for incident light, i.e., when irradiated by left‐circularly polarized light, l ‐Cys‐MoO_3?x is the most sensitive agent giving the highest mortality for HeLa cell ablation in vitro, and vice versa for right‐circularly polarized light with d ‐Cys‐MoO_3?x. In comparison to traditional photothermal therapy with near‐field light source, the investigations with chiral visible light at 532 nm indicate the possibility of chiral Cys‐MoO_3?x nanoparticles for visible light‐based phototherapy via metal–ligand charge transfer chirality, which provides insights for new methods in nanotechnology supported photothermal treatments.     

Ultra‐Small Iron Oxide Doped Polypyrrole Nanoparticles for In Vivo Multimodal Imaging Guided Photothermal Therapy

Recently, near‐infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR‐absorbing conjugate polymer, is used to coat ultra‐small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer‐by‐layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy‐PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor‐bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR‐absorbing organic‐inorganic hybrid nanomaterials, such as IONP@PPy‐PEG presented here, for potential applications in cancer theranostics.     

Increasing Photothermal Efficacy by Simultaneous Intra‐ and Intermolecular Fluorescence Quenching

Recently, using in situ self‐assembly‐induced fluorescence quenching (i.e., intermolecular quenching denoted herein) of a photothermal agent (PTA) to enhance its photothermal efficiency has proven to be a successful photothermal therapy (PTT) strategy. But to the best of current knowledge, using simultaneous intra‐ and intermolecular fluorescence quenching of a PTA to additionally increase its photothermal efficacy has not been reported. Herein, employing a click condensation reaction and a rationally designed PTA Biotin‐Cystamine‐Cys‐Lys(Cypate)‐CBT ( 1 ), a “smart” strategy is developed of intracellular simultaneous intra‐ and intermolecular fluorescence quenching and applied it to largely increase the photothermal efficacy of the agent both in vitro and in vivo. After being internalized by biotin receptor‐overexpressing cancer cells, 1 is reduced by intracellular glutathione to initiate a CBT‐Cys condensation reaction (intramolecular quenching) and self‐assembly (intermolecular quenching) to form the nanoparticles 1‐NPs (simultaneous intra‐ and intermolecular fluorescence quenching). Experimental results indicate that 1‐NPs have higher fluorescence quenching efficiency than the control PTAs [Thiazole‐Lys(Cypate)‐Benzothiazole]₂ ( 1‐Dimer , intramolecular quenching), and nanoparticles of Cystamine‐Cys(Fmoc)‐Lys(Cypate)‐CBT ( 1‐Fmoc‐NPs , intermolecular quenching). It is envisioned that, by replacing the biotin group on 1 with other targeting warheads, the “smart” strategy is ready to increase the photothermal therapeutic efficiency of their corresponding diseases.     

Enhanced Physiochemical and Mechanical Performance of Chitosan‐Grafted Graphene Oxide for Superior Osteoinductivity

The regeneration of artificial bone substitutes is a potential strategy for repairing bone defects. However, the development of substitutes with appropriate osteoinductivity and physiochemical properties, such as water uptake and retention, mechanical properties, and biodegradation, remains challenging. Therefore, there is a motivation to develop new synthetic grafts that possess good biocompatibility, physiochemical properties, and osteoinductivity. Here, we fabricate a biocompatible scaffold through the covalent crosslinking of graphene oxide (GO) and carboxymethyl chitosan (CMC). The resulting GO‐CMC scaffold shows significant high water retention (44% water loss) compared with unmodified CMC scaffolds (120% water loss) due to a steric hindrance effect. The modulus and hardness of the GO‐CMC scaffold are 2.75‐ and 3.51‐fold higher, respectively, than those of the CMC scaffold. Furthermore, the osteoinductivity of the GO‐CMC scaffold is enhanced due to the π–π stacking interactions of the GO sheets, which result in striking upregulation of osteogenesis‐related genes, including osteopontin, bone sialoprotein, osterix, osteocalcin, and alkaline phosphatase. Finally, the GO‐CMC scaffold exhibits excellent reparative effects in repairing rat calvarial defects via the synergistic effects of GO and bone morphogenetic protein‐2. This study provides new insights for developing bone substitutes for tissue engineering and regenerative medicine.     

Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH‐Responsive Theranostic Platform

A unique mesoporous silica nanoparticles (MSNs)‐based theranostic platform with ultrasmall iron oxide nanoparticles (NPs) confined within mesopore network has been developed by a facile but efficient physical‐vapor‐infiltration (PVI) method. The highly dispersed Fe species within mesopore channels can synchronously function as the non‐toxic contrast agents for highly efficient T₁‐weighted MR imaging, and as anchoring sites for anti‐cancer drug molecule loading and pH‐responsive release based on the special metal‐ligand coordination bonding between the Fe species and drug molecules. Moreover, the obtained Fe‐MSNs exhibit favorable biocompatibility, enhanced chemotherapeutic efficacy and concurrently diminished side effects due to the non‐specific attack of chemotherapeutic drugs, as well as the capability in circumventing the multidrug resistance (MDR) of cancer cells and suppressing the metastasis of tumor cells in vitro and in vivo. This pH‐resoponsive theranostic agent provides a new promising MSNs‐based anti‐cancer nanomedicine for future biomedical application.     

Luminescent Graphene Oxide with a Peptide‐Quencher Complex for Optical Detection of Cell‐Secreted Proteases by a Turn‐On Response

Graphene oxide (GO) is an emerging luminescent nanomaterial with photostable and unique photoluminescence (PL) in the visible and near‐infrared region. Herein, a GO PL‐based optical biosensor consisting of a luminescent GO donor covalently linked with a peptide‐quencher complex is reported for the simple, rapid, and sensitive detection of proteases. To this end, the quenching efficiency of various candidate quenchers of GO fluorescence, such as metalloprotoporphyrins and QXL₅₇₀, are examined and their quenching mechanisms investigated. A fluorescence resonance energy transfer‐based quencher, QXL₅₇₀, is found to be much more effective for quenching the intrinsic fluorescence of GO than other charge transfer‐based quenchers. The designed GO–peptide–QXL system is then able to sensitively detect specific proteases—chymotrypsin and matrix metalloproteinase‐2—via a “turn‐on” response of quenched GO fluorescence after proteolytic cleavage of the quencher. Finally, the GO–peptide–QXL hybrid successfully detects MMP‐2 secreted from living cells—human hepatocytes HepG2—with high sensitivity.     

pH‐Responsive Peptide Mimic Shell Cross‐Linked Magnetic Nanocarriers for Combination Therapy

The design and development of water dispersible, pH responsive peptide mimic shell cross‐linked magnetic nanocarriers (PMNCs) using a facile soft‐chemical approach is reported. These nanocarriers have an average size about 10 nm, are resistant to protein adsorption in physiological medium, and transform from a negatively charged to a positively charged form in the acidic environment. The terminal amino acid on the shell of the magnetic nanocarriers allows us to create functionalized exteriors with high densities of organic moieties (both amine and carboxyl) for conjugation of drug molecules. The drug‐loading efficiency of the nanocarriers is investigated using doxorubicin hydrochloride (DOX) as a model drug to evaluate their potential as a carrier system. Results show high loading affinity of nanocarriers for anticancer drug, their sustained release profile, magnetic‐field‐induced heating, and substantial cellular internalization. Moreover, the enhanced toxicity to tumor cells by DOX‐loaded PMNCs (DOX‐PMNCs) under an AC magntic field suggest their potential for combination therapy involving hyperthermia and chemotherapy.     

Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics

Construction of multifunctional stimuli‐responsive nanosystems intelligently responsive to inner physiological and/or external irradiations based on nanobiotechnology can enable the on‐demand drug release and improved diagnostic imaging to mitigate the side‐effects of anticancer drugs and enhance the diagnostic/therapeutic outcome simultaneously. Here, a triple‐functional stimuli‐responsive nanosystem based on the co‐integration of superparamagnetic Fe₃O₄ and paramagnetic MnO_x nanoparticles (NPs) onto exfoliated graphene oxide (GO) nanosheets by a novel and efficient double redox strategy (DRS) is reported. Aromatic anticancer drug molecules can interact with GO nanosheets through supramolecular π stacking to achieve high drug loading capacity and pH‐responsive drug releasing performance. The integrated MnO_x NPs can disintegrate in mild acidic and reduction environment to realize the highly efficient pH‐responsive and reduction‐triggered T₁‐weighted magnetic resonance imaging (MRI). Superparamagnetic Fe₃O₄ NPs can not only function as the T₂‐weighted contrast agents for MRI, but also response to the external magnetic field for magnetic hyperthermia against cancer. Importantly, the constructed biocompatible GO‐based nanoplatform can inhibit the metastasis of cancer cells by downregulating the expression of metastasis‐related proteins, and anticancer drug‐loaded carrier can significantly reverse the multidrug resistance (MDR) of cancer cells.     

Redox Sensitive Hyaluronic Acid‐Decorated Graphene Oxide for Photothermally Controlled Tumor‐Cytoplasm‐Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox‐sensitive, hyaluronic acid‐decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm‐specific rapid delivery using near‐infrared (NIR) irradiation controlled endo/lysosome disruption and redox‐triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox‐sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug‐loading capacity for aromatic molecules, HA receptor‐mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox‐dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA‐receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm‐specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox‐triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.     

Nanostructural Control Enables Optimized Photoacoustic–Fluorescence–Magnetic Resonance Multimodal Imaging and Photothermal Therapy of Brain Tumor

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near‐infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF‐cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF‐cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.     

Self‐Mineralized Photothermal Bacteria Hybridizing with Mitochondria‐Targeted Metal–Organic Frameworks for Augmenting Photothermal Tumor Therapy

A photothermal bacterium (PTB) is reported for tumor‐targeted photothermal therapy (PTT) by using facultative anaerobic bacterium Shewanella oneidensis MR‐1 (S. oneidensis MR‐1) to biomineralize palladium nanoparticles (Pd NPs) on its surface without affecting bacterial activity. It is found that PTB possesses superior photothermal property in near infrared (NIR) regions, as well as preferential tumor‐targeting capacity. Zeolitic imidazole frameworks‐90 (ZIF‐90) encapsulating photosensitizer methylene blue (MB) are hybridized on the surface of living PTB to further enhance PTT efficacy. MB‐encapsulated ZIF‐90 (ZIF‐90/MB) can selectively release MB at mitochondria and cause mitochondrial dysfunction by producing singlet oxygen (¹O₂) under light illumination. Mitochondrial dysfunction further contributes to adenosine triphosphate (ATP) synthesis inhibition and heat shock proteins (HSPs) down‐regulated expression. The PTB‐based therapeutic platform of PTB@ZIF‐90/MB demonstrated here will find great potential to overcome the challenges of tumor targeting and tumor heat tolerance in PTT.     

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.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

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.     

Conjugated Polymer Nanoparticle–Graphene Oxide Charge‐Transfer Complexes

The game‐changing role of graphene oxide (GO) in tuning the excitonic behavior of conjugated polymer nanoparticles is described for the first time. This is demonstrated by using poly(3‐hexylthiophene) (P3HT) as a benchmark conjugated polymer and employing an in situ reprecipitation approach resulting in P3HT nanoparticles (P3HT_NPs) with sizes of 50–100 nm in intimate contact with GO. During the self‐assembly process, GO changes the crystalline packing of P3HT chains in the forming P3HT_NPs from H to H/J aggregates exhibiting exciton coupling constants as low as 2 meV, indicating favorable charge separation along the P3HT chains. Concomitantly, π–π interface interactions between the P3HT_NPs and GO sheets are established resulting in the creation of P3HT_NPs–GO charge‐transfer complexes whose energy bandgaps are lowered by up to 0.5 eV. Moreover, their optoelectronic properties, preestablished in the liquid phase, are retained when processed into thin films from the stable aqueous dispersions, thus eliminating the critical dependency on external processing parameters. These results can be transferred to other types of conjugated polymers. Combined with the possibility of employing water based “green” processing technologies, charge‐transfer complexes of conjugated polymer nanoparticles and GO open new pathways for the fabrication of improved optoelectronic thin film devices.     

Cancer Stem Cell‐Platelet Hybrid Membrane‐Coated Magnetic Nanoparticles for Enhanced Photothermal Therapy of Head and Neck Squamous Cell Carcinoma

Cell membrane–based nanosystems with desirable characteristics have been studied extensively for many therapeutic applications. However, current research has focused on single cell membrane, and multifunctional fused membrane materials from different membrane types are still rare. Herein, a platelet–cancer stem cell (CSC) hybrid membrane‐coated iron oxide magnetic nanoparticle (MN) {[CSC‐P]MN} is presented for the first time for the enhanced photothermal therapy of head and neck squamous cell carcinoma (HNSCC). Inherited from the original source cells, the platelet membrane shows immune evading ability due to the surface marker comprising a number of “don't eat me” signals, and the CSC membrane has homotypic targeting capabilities due to the specific surface adhesion molecules. The [CSC‐P]MNs possess superior characteristics for immune evasion, active cancer targeting, magnetic resonance imaging, and photothermal therapy. Compared with single cell membrane–coated MNs, [CSC‐P]MNs exhibit prolonged circulation times and enhanced targeting abilities. Moreover, the [CSC‐P]MNs exhibit a superior photothermal ability that provides excellent HNSCC tumor growth inhibition, particularly in an immunocompetent Tgfbr1/Pten conditional double knockout HNSCC mouse model that contains a more complex tumor microenvironment that is similar to the human HNSCC microenvironment. Collectively, this biomimetic multimembrane‐coated nanoplatform may provide enhanced antitumor efficacy in the complex tumor microenvironment.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.