Light‐Triggered Biomimetic Nanoerythrocyte for Tumor‐Targeted Lung Metastatic Combination Therapy of Malignant Melanoma

Red blood cell (RBC) membrane‐cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell‐specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2‐diaminocyclohexane‐platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide‐modified erythrocyte membrane (R‐RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R‐RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R‐RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near‐infrared laser stimuli, R‐RBC@BPtI presents remarkable instability by singlet oxygen and heat‐mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R‐RBC@BPtI with tumor‐specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy–phototherapy.     

J‐Aggregates of Organic Dye Molecules Complexed with Iron Oxide Nanoparticles for Imaging‐Guided Photothermal Therapy Under 915‐nm Light

Recently, the development of nano‐theranostic agents aiming at imaging guided therapy has received great attention. In this work, a near‐infrared (NIR) heptamethine indocyanine dye, IR825, in the presence of cationic polymer, polyallylamine hydrochloride (PAH), forms J‐aggregates with red‐shifted and significantly enhanced absorbance. After further complexing with ultra‐small iron oxide nanoparticles (IONPs) and the followed functionalization with polyethylene glycol (PEG), the obtained IR825@PAH‐IONP‐PEG composite nanoparticles are highly stable in different physiological media. With a sharp absorbance peak, IR825@PAH‐IONP‐PEG can serve as an effective photothermal agent under laser irradiation at 915 nm, which appears to be optimal in photothermal therapy application considering its improved tissue penetration compared with 808‐nm light and much lower water heating in comparison to 980‐nm light. As revealed by magnetic resonance (MR) imaging, those nanoparticles after intravenous injection exhibit high tumor accumulation, which is then harnessed for in vivo photothermal ablation of tumors, achieving excellent therapeutic efficacy in a mouse tumor model. This study demonstrates for the first time that J‐aggregates of organic dye molecules are an interesting class of photothermal material, which when combined with other imageable nanoprobes could serve as a theranostic agent for imaging‐guided photothermal therapy of cancer.     

A Hollow‐Structured CuS@Cu2S@Au Nanohybrid: Synergistically Enhanced Photothermal Efficiency and Photoswitchable Targeting Effect for Cancer Theranostics

It is of great importance in drug delivery to fabricate multifunctional nanocarriers with intelligent targeting properties, for cancer diagnosis and therapy. Herein, hollow‐structured CuS@Cu₂S@Au nanoshell/satellite nanoparticles are designed and synthesized for enhanced photothermal therapy and photoswitchable targeting theranostics. The remarkably improved photothermal conversion efficiency of CuS@Cu₂S@Au under 808 nm near‐infrared (NIR) laser irradiation can be explained by the reduced bandgap and more circuit paths for electron transitions for CuS and Cu₂S modified with Au nanoparticles, as calculated by the Vienna ab initio simulation package, based on density functional theory. By modification of thermal‐isomerization RGD targeting molecules and thermally sensitive copolymer on the surface of nanoparticles, the transition of the shielded/unshielded mode of RGD (Arg‐Gly‐Asp) targeting molecules and shrinking of the thermally sensitive polymer by NIR photoactivation can realize a photoswitchable targeting effect. After loading an anticancer drug doxorubicin in the cavity of CuS@Cu₂S@Au, the antitumor therapy efficacy is greatly enhanced by combining chemo‐ and photothermal therapy. The reported nanohybrid can also act as a photoacoustic imaging agent and an NIR thermal imaging agent for real‐time imaging, which provides a versatile platform for multifunctional theranostics and stimuli‐responsive targeted cancer therapy.     

Heat profiling of three-dimensionally optically trapped gold nanoparticles using vesicle cargo release

Irradiated metallic nanoparticles hold great promise as heat transducers in photothermal applications such as drug delivery assays or photothermal therapy. We quantify the temperature increase of individual gold nanoparticles trapped in three dimensions near lipid vesicles exhibiting temperature sensitive permeability. The surface temperature can increase by hundreds of degrees Celsius even at moderate laser powers. Also, there are significant differences of the heat profiles in two-dimensional and three-dimensional trapping assays.     

Let There be Light: Polymeric Micelles with Upper Critical Solution Temperature as Light‐Triggered Heat Nanogenerators for Combating Drug‐Resistant Cancer

Complete drug release and efficient drug retention are two critical factors in reversing drug resistance in cancer therapy. In this regard, polymeric micelles with an upper critical solution temperature (UCST) are designed as a new exploration to reverse drug resistance. The amphiphilic UCST‐type block copolymers are used to encapsulate photothermal agent IR780 and doxorubicin (DOX) simultaneously. The integrated UCST‐type drug nanocarriers show light‐triggered multiple synergistic effects to reverse drug resistance and are expected to kill three birds with one stone: First, owing to the photothermal effect of IR780, the nanocarriers will be dissociated upon exposure to laser irradiation, leading to complete drug release. Second, the photothermal effect‐induced hyperthermia is expected to avoid the efflux of DOX and realize efficient drug retention. Last but not least, photothermal ablation of cancer cells can be achieved after laser irradiation. Therefore, the UCST‐type drug nanocarriers provide a new strategy in reversing drug resistance in cancer therapy.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Facile synthesis of hydrophilic polypyrrole nanoparticles for photothermal cancer therapy

PPY nanoparticles, as one of the important organic photothermal agents has been attracted great attention due to their good biocompatibility, high photothermal efficiency, and low cost. In order to further evaluate the size-dependent photothermal effect, PPY nanoparticles with two different sizes have been prepared with a facile method. The near infrared absorption and photothermal effect of the two size PPY nanoparticles were compared. The PPY nanoparticle with small size shows better photothermal effect at the same condition. The photostability, stability, and cytotoxicity in biologic system have also been investigated. In addition, the PPY nanoparticles with small size can kill the cancer cells effectively under the irradiation of 808 nm laser with a low-power density. These findings may provide better information for the application of the PPY nanoparticles on the photothermal ablation of cancer cells.     

Flexible Photothermal Assemblies with Tunable Gold Patterns for Improved Imaging‐Guided Synergistic Therapy

Self‐assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic‐co‐glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion‐confined and polymer‐directed self‐assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid‐modified R‐PLGA‐Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real‐time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT‐enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging‐guided synergistic therapy.     

A Novel Top‐Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging‐Guided Cancer Therapy

Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top‐down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR‐light‐to‐heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug‐loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top‐down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging‐guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications.     

Drug‐Controlled Release Based on Complementary Base Pairing Rules for Photodynamic–Photothermal Synergistic Tumor Treatment

Controlled drug release systems can enhance the safety and availability but avoid the side effect of drugs. Herein, the concept of DNA complementary base pairing rules in biology is used to design and prepare a photothermal‐triggered drug release system. Adenine (A) modified polydopamine nanoparticles (A‐PDA, photothermal reagent) can effectively bind with thymine (T) modified Zinc phthalocyanine (T‐ZnPc, photosensitizer) forming A‐PDA = T‐ZnPc (PATP) complex based on A = T complementary base pairing rules. Similar to DNA, whose base pairing in double strands will break by heating, T‐ZnPc can be effectively released from A‐PDA after near infrared irradiation–triggered light‐thermal conversion to obtain satisfactory photodynamic–photothermal synergistic tumor treatment. In addition, PDA can carry abundant Gd³⁺ to provide magnetic resonance imaging guided delivery and theranostic function.     

Through Scalp and Skull NIR‐II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

Brain tumor is one of the most lethal cancers owing to the existence of blood–brain barrier and blood–brain tumor barrier as well as the lack of highly effective brain tumor treatment paradigms. Herein, cyclo(Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)) decorated biocompatible and photostable conjugated polymer nanoparticles with strong absorption in the second near‐infrared (NIR‐II) window are developed for precise photoacoustic imaging and spatiotemporal photothermal therapy of brain tumor through scalp and skull. Evidenced by the higher efficiency to penetrate scalp and skull for 1064 nm laser as compared to common 808 nm laser, NIR‐II brain‐tumor photothermal therapy is highly effective. In addition, via a real‐time photoacoustic imaging system, the nanoparticles assist clear pinpointing of glioma at a depth of almost 3 mm through scalp and skull with an ultrahigh signal‐to‐background ratio of 90. After spatiotemporal photothermal treatment, the tumor progression is effectively inhibited and the survival spans of mice are significantly extended. This study demonstrates that NIR‐II conjugated polymer nanoparticles are promising for precise imaging and treatment of brain tumors.     

A Smart Responsive Dual Aptamers‐Targeted Bubble‐Generating Nanosystem for Cancer Triplex Therapy and Ultrasound Imaging

The absence of targeted, single treatment methods produces low therapeutic value for treating cancers. To increase the accumulation of drugs in tumors and improve the treatment effectiveness, near‐infrared 808 nm photothermal responsive dual aptamers‐targeted docetaxel (DTX)‐containing nanoparticles is proposed. In this system, DTX and NH₄HCO₃ are loaded in thermosensitive liposomes. The surface of liposomes is coated with gold nanoshells and connected with sulfydryl (SH? ) modified AS1411 and S2.2 aptamers. The nanosystem has good biocompatibility and uniform size (diameter about 200 nm). The drug is rapidly released, reaching a maximum amount (84%) at 4 h under 808 nm laser irradiation. The experiments conducted in vitro and in vivo demonstrate the nanosystem can synergistically inhibit tumor growth by combination of chemotherapy, photothermal therapy, and biological therapy. Dual ligand functionalization significantly increases cellular uptake on breast cancer cell line (MCF‐7) cells and achieves ultrasound imaging (USI) at tumor site. The results indicate that this drug delivery system is a promising theranostic agent involving light‐thermal response at tumor sites, dual ligand targeted triplex therapy, and USI.     

Sub‐10‐nm Pd Nanosheets with Renal Clearance for Efficient Near‐Infrared Photothermal Cancer Therapy

Efficient renal clearance is of fundamentally important property of nanoparticles for their in vivo biomedical applications. In this work, we report the successful synthesis of ultra‐small Pd nanosheets (SPNS) with an average diameter of 4.4 nm and their application in photothermal cancer therapy using a near infrared laser. The ultra‐small Pd nanosheets have strong optical absorption in the NIR region and high photothermal conversion efficiency (52.0%) at 808 nm. After being surface‐functionalized with reduced glutathione (GSH), the SPNS‐GSH was administered to mice to investigate the biodistribution, photothermal efficacy and tumor ablation in vivo. The in vivo photothermal therapy studies clearly demonstrate that surface modification with GSH allows the nanosheets to exhibit prolonged blood circulation and thus high accumulation in tumors. Upon 808 nm NIR irradiation, the tumors can be completely ablated. More importantly, with the size below the renal filtration limit (<10 nm), the GSHylated Pd nanosheets can be nicely cleared from body through the renal excretion route and into urine. Together with the high efficacy of NIR photothermal therapy, the unique renal clearance properties make the ultra‐small Pd nanosheets promising for practical use in photothermal cancer therapy.     

A Eutectic Mixture of Natural Fatty Acids Can Serve as the Gating Material for Near‐Infrared‐Triggered Drug Release

A smart release system responsive to near‐infrared (NIR) light is developed for intracellular drug delivery. The concept is demonstrated by coencapsulating doxorubicin (DOX) (an anticancer drug) and IR780 iodide (IR780) (an NIR‐absorbing dye) into nanoparticles made of a eutectic mixture of naturally occurring fatty acids. The eutectic mixture has a well‐defined melting point at 39 °C, and can be used as a biocompatible phase‐change material for NIR‐triggered drug release. The resultant nanoparticles exhibit prominent photothermal effect and quick drug release in response to NIR irradiation. Fluorescence microscopy analysis indicates that the DOX trapped in the nanoparticles can be efficiently released into the cytosol under NIR irradiation, resulting in enhanced anticancer activity. A new platform is thus offered for designing effective intracellular drug‐release systems, holding great promise for future cancer therapy.     

Near‐Infrared‐Resonant Gold/Gold Sulfide Nanoparticles as a Photothermal Cancer Therapeutic Agent

The development and optimization of near‐infrared (NIR)‐absorbing nanoparticles for use as photothermal cancer therapeutic agents has been ongoing. This work exploits the properties of gold/gold sulfide NIR‐absorbing nanoparticles (≈35–55 nm) that provide higher absorption (98% absorption and 2% scattering for gold/gold sulfide versus 70% absorption and 30% scattering for gold/silica nanoshells) as well as potentially better tumor penetration. The ability to ablate tumor cells in vitro and efficacy for photothermal cancer therapy is demonstrated, and an in vivo model shows significantly increased long‐term, tumor‐free survival. Furthermore, enhanced circulation and biodistribution is observed in vivo. This class of NIR‐absorbing nanoparticles has the potential to improve upon photothermal tumor ablation for cancer therapy.     

Cyanine‐Anchored Silica Nanochannels for Light‐Driven Synergistic Thermo‐Chemotherapy

Smart nanoparticles are increasingly important in a variety of applications such as cancer therapy. However, it is still a major challenge to develop light‐responsive nanoparticles that can maximize the potency of synergistic thermo‐chemotherapy under light irradiation. Here, spatially confined cyanine‐anchored silica nanochannels loaded with chemotherapeutic doxorubicin (CS‐DOX‐NCs) for light‐driven synergistic cancer therapy are introduced. CS‐DOX‐NCs possess a J‐type aggregation conformation of cyanine dye within the nanochannels and encapsulate doxorubicin through the π–π interaction with cyanine dye. Under near‐infrared light irradiation, CS‐DOX‐NCs produce the enhanced photothermal conversion efficiency through the maximized nonradiative transition of J‐type Cypate aggregates, trigger the light‐driven drug release through the destabilization of temperature‐sensitive π–π interaction, and generate the effective intracellular translocation of doxorubicin from the lysosomes to cytoplasma through reactive oxygen species‐mediated lysosomal disruption, thereby causing the potent in vivo hyperthermia and intracellular trafficking of drug into cytoplasma at tumors. Moreover, CS‐DOX‐NCs possess good resistance to photobleaching and preferable tumor accumulation, facilitating severe photoinduced cell damage, and subsequent synergy between photothermal and chemotherapeutic therapy with tumor ablation. These findings provide new insights of light‐driven nanoparticles for synergistic cancer therapy.     

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.     

Super‐Resolution Nonlinear Photothermal Microscopy

Super‐resolution fluorescence microscopy enables imaging of fluorescent structures beyond the diffraction limit. However, this technique cannot be applied to weakly fluorescent cellular components or labels. As an alternative, photothermal microscopy based on nonradiative transformation of absorbed energy into heat has demonstrated imaging of nonfluorescent structures including single molecules and ~1‐nm gold nanoparticles. However, previously photothermal imaging has been performed with a diffraction‐limited resolution only. Herein, super‐resolution, far‐field photothermal microscopy based on nonlinear signal dependence on the laser energy is introduced. Among various nonlinear phenomena, including absorption saturation, multiphoton absorption, and signal temperature dependence, signal amplification by laser‐induced nanobubbles around overheated nano‐objects is explored. A Gaussian laser beam profile is used to demonstrate the image spatial sharpening for calibrated 260‐nm metal strips, resolving of a plasmonic nanoassembly, visualization of 10‐nm gold nanoparticles in graphene, and hemoglobin nanoclusters in live erythrocytes with resolution down to 50 nm. These nonlinear phenomena can be used for 3D imaging with improved lateral and axial resolution in most photothermal methods, including photoacoustic microscopy.     

Graphene Quantum Dots‐Capped Magnetic Mesoporous Silica Nanoparticles as a Multifunctional Platform for Controlled Drug Delivery,Magnetic Hyperthermia,and Photothermal Therapy

A multifunctional platform is reported for synergistic therapy with controlled drug release, magnetic hyperthermia, and photothermal therapy, which is composed of graphene quantum dots (GQDs) as caps and local photothermal generators and magnetic mesoporous silica nanoparticles (MMSN) as drug carriers and magnetic thermoseeds. The structure, drug release behavior, magnetic hyperthermia capacity, photothermal effect, and synergistic therapeutic efficiency of the MMSN/GQDs nanoparticles are investigated. The results show that monodisperse MMSN/GQDs nanoparticles with the particle size of 100 nm can load doxorubicin (DOX) and trigger DOX release by low pH environment. Furthermore, the MMSN/GQDs nanoparticles can efficiently generate heat to the hyperthermia temperature under an alternating magnetic field or by near infrared irradiation. More importantly, breast cancer 4T1 cells as a model cellular system, the results indicate that compared with chemotherapy, magnetic hyperthermia or photothermal therapy alone, the combined chemo‐magnetic hyperthermia therapy or chemo‐photothermal therapy with the DOX‐loaded MMSN/GQDs nanosystem exhibits a significant synergistic effect, resulting in a higher efficacy to kill cancer cells. Therefore, the MMSN/GQDs multifunctional platform has great potential in cancer therapy for enhancing the therapeutic efficiency.     

Gold Nanorods Coated with Mesoporous Silica Shell as Drug Delivery System for Remote Near Infrared Light‐Activated Release and Potential Phototherapy

In this study, we report the synthesis of a nanoscaled drug delivery system, which is composed of a gold nanorod‐like core and a mesoporous silica shell (GNR@MSNP) and partially uploaded with phase‐changing molecules (1‐tetradecanol, TD, T_m 39 °C) as gatekeepers, as well as its ability to regulate the release of doxorubicin (DOX). Indeed, a nearly zero premature release is evidenced at physiological temperature (37 °C), whereas the DOX release is efficiently achieved at higher temperature not only upon external heating, but also via internal heating generated by the GNR core under near infrared irradiation. When tagged with folate moieties, GNR@MSNPs target specifically to KB cells, which are known to overexpress the folate receptors. Such a precise control over drug release, combining with the photothermal effect of GNR cores, provides promising opportunity for localized synergistic photothermal ablation and chemotherapy. Moreover, the performance in killing the targeted cancer cells is more efficient compared with the single phototherapeutic modality of GNR@MSNPs. This versatile combination of local heating, phototherapeutics, chemotherapeutics and gating components opens up the possibilities for designing multifunctional drug delivery systems.