Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy.

Immunogenic cell death (ICD) elicited by photodynamic therapy (PDT) is mediated through generation of reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress. However, the half-life of ROS is very short and the intracellular diffusion depth is limited, which impairs ER localization and thus limits ER stress induction. To solve the problem, we synthesized reduction-sensitive Ds-sP NPs (PEG-s-s-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-TER (4,4',4″,4'″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide). The resulting Ds-sP/TCPP-TER NPs could selectively accumulate in the ER and locally generate ROS under near-infrared (NIR) laser irradiation, which induced ER stress, amplified ICD, and activated immune cells, leading to augmented immunotherapy effect. This study presents a novel ICD amplifying, ER-targeting PDT strategy that can effectively eradicate primary tumors under NIR exposure, as well as distant tumors through an abscopal effect.

Synthesis of Copper Peroxide Nanodots for H2O2 Self-Supplying Chemodynamic Therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

Enhanced Antitumor Efficacy by a Cascade of Reactive Oxygen Species Generation and Drug Release.

Reactive oxygen species (ROS) can be used not only as a therapeutic agent for chemodynamic therapy (CDT), but also as a stimulus to activate release of antitumor drugs, achieving enhanced efficacy through the combination of CDT and chemotherapy. Here we report a pH/ROS dual-responsive nanomedicine consisting of ß-lapachone (Lap), a pH-responsive polymer, and a ROS-responsive polyprodrug. In the intracellular acidic environment, the nanomedicine can realize pH-triggered disassembly. The released Lap can efficiently generate hydrogen peroxide, which will be further converted into highly toxic hydroxyl radicals via the Fenton reaction. Subsequently, through ROS-induced cleavage of thioketal linker, doxorubicin is released from the polyprodrug. In vivo results indicate that the cascade of ROS generation and antitumor-drug release can effectively inhibit tumor growth. This design of nanomedicine with cascade reactions offers a promising strategy to enhance antitumor efficacy.

Porphyrin Nanocage-Embedded Single-Molecular Nanoparticles for Cancer Nanotheranostics.

Single molecular nanoparticles (SMNPs) integrating imaging and therapeutic capabilities exhibit unparalleled advantages in cancer theranostics, ranging from excellent biocompatibility, high stability, prolonged blood lifetime to abundant tumor accumulation. Herein, we synthesize a sophisticated porphyrin nanocage that is further functionalized with twelve polyethylene glycol arms to prepare SMNPs (porSMNPs). The porphyrin nanocage embedded in porSMNPs can be utilized as a theranostic platform. PET imaging allows dynamic observation of the bio-distribution of porSMNPs, confirming their excellent circulation time and preferential accumulation at the tumor site, which is attributed to the enhanced permeability and retention effect. Moreover, the cage structure significantly promotes the photosensitizing effect of porSMNs by inhibiting the π-π stacking interactions of the photosensitizers, ablating of the tumors without relapse by taking advantage of photodynamic therapy.

Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2 -Based Nanoagent to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) utilizes iron-initiated Fenton chemistry to destroy tumor cells by converting endogenous H2 O2 into the highly toxic hydroxyl radical (. OH). There is a paucity of Fenton-like metal-based CDT agents. Intracellular glutathione (GSH) with . OH scavenging ability greatly reduces CDT efficacy. A self-reinforcing CDT nanoagent based on MnO2 is reported that has both Fenton-like Mn2+ delivery and GSH depletion properties. In the presence of HCO3- , which is abundant in the physiological medium, Mn2+ exerts Fenton-like activity to generate . OH from H2 O2 . Upon uptake of MnO2 -coated mesoporous silica nanoparticles (MS@MnO2 NPs) by cancer cells, the MnO2 shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn2+ , resulting in GSH depletion-enhanced CDT. This, together with the GSH-activated MRI contrast effect and dissociation of MnO2 , allows MS@MnO2 NPs to achieve MRI-monitored chemo-chemodynamic combination therapy.

Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy.

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

Yolk-Shell Nanostructures: Design, Synthesis, and Biomedical Applications.

Yolk-shell nanostructures (YSNs) composed of a core within a hollow cavity surrounded by a porous outer shell have received tremendous research interest owing to their unique structural features, fascinating physicochemical properties, and widespread potential applications. Here, a comprehensive overview of the design, synthesis, and biomedical applications of YSNs is presented. The synthetic strategies toward YSNs are divided into four categories, including hard-templating, soft-templating, self-templating, and multimethod combination synthesis. For the hard- or soft-templating strategies, different types of rigid or vesicle templates are used for making YSNs. For the self-templating strategy, a number of unconventional synthetic methods without additional templates are introduced. For the multimethod combination strategy, various methods are applied together to produce YSNs that cannot be obtained directly by only a single method. The biomedical applications of YSNs including biosensing, bioimaging, drug/gene delivery, and cancer therapy are discussed in detail. Moreover, the potential superiority of YSNs for these applications is also highlighted. Finally, some perspectives on the future research and development of YSNs are provided.

Hierarchical Tumor Microenvironment-Responsive Nanomedicine for Programmed Delivery of Chemotherapeutics.

Nanomedicines have been demonstrated to have passive or active tumor targeting behaviors, which are promising for cancer chemotherapy. However, most nanomedicines still suffer from a suboptimal targeting effect and drug leakage, resulting in unsatisfactory treatment outcome. Herein, a hierarchical responsive nanomedicine (HRNM) is developed for programmed delivery of chemotherapeutics. The HRNMs are prepared via the self-assembly of cyclic Arg-Gly-Asp (RGD) peptide conjugated triblock copolymer, poly(2-(hexamethyleneimino)ethyl methacrylate)-poly(oligo-(ethylene glycol) monomethyl ether methacrylate)-poly[reduction-responsive camptothecin] (PC7A-POEG-PssCPT). In blood circulation, the RGD peptides are shielded by the POEG coating; therefore, the nanosized HRNMs can achieve effective tumor accumulation through passive targeting. Once the HRNMs reach a tumor site, due to the hydrophobic-tohydrophilic conversion of PC7A chains induced by the acidic tumor microenvironment, the RGD peptides will be exposed for enhanced tumor retention and cellular internalization. Moreover, in response to the glutathione inside cells, active CPT drugs will be released rapidly for chemotherapy. The in vitro and in vivo results confirm effective tumor targeting, potent antitumor effect, and reduced systemic toxicity of the HRNMs. This HRNM is promising for enhanced chemotherapeutic delivery.

Yolk-Shell Nanostructure: An Ideal Architecture to Achieve Harmonious Integration of Magnetic-Plasmonic Hybrid Theranostic Platform.

Magnetic-plasmonic hybrid nanoparticles (MPHNs) have attracted great interest in cancer theranostics. However, the relaxivity of the magnetic component is typically reduced by the plasmonic component in conventional core-shell structured MPHNs, due to the presence of a water-impenetrable coating which severely restricts the proximity of protons to the magnetic portion. To circumvent this issue, yolk-shell structured MPHNs comprising a Fe3 O4 core within a hollow cavity encircled by a porous Au outer shell are designed. As expected, the introduction of hollow cavity between the magnetic and plasmonic portions significantly prevents the decline in relaxivity of the Fe3 O4 core caused by the Au layer. Moreover, in addition to conferring high near-infrared absorption to plasmonic component, the hollow cavity and the pores in the outer shell can also provide a large storage space and release channels for anticancer drugs. Furthermore, the multicomponent nanoparticles (NPs) still have a compact size of less than 100 nm to ensure efficient tumor accumulation. Taken together, the yolk-shell Fe3 O4 @Au NPs can be regarded as an ideal magnetic-plasmonic theranostic platform for magnetic resonance/photoacoustic/positron emission tomography multimodal imaging and light-activated chemothermal synergistic therapy.

Dual-enhanced photothermal conversion properties of reduced graphene oxide-coated gold superparticles for light-triggered acoustic and thermal theranostics.

A rational design of highly efficient photothermal agents that possess excellent light-to-heat conversion properties is a fascinating topic in nanotheranostics. Herein, we present a facile route to fabricate size-tunable reduced graphene oxide (rGO)-coated gold superparticles (rGO-GSPs) and demonstrate their dual-enhanced photothermal conversion properties for photoacoustic imaging and photothermal therapy. For the first time, graphene oxide (GO) was directly used as an emulsifying agent for the preparation of gold superparticles (GSPs) with near-infrared absorption by the emulsion method. Moreover, GO spontaneously deposited on the surface of GSPs could also act as the precursor of the rGO shell. Importantly, both the plasmonic coupling of the self-assembled gold nanoparticles and the interaction between GSPs and rGO endow rGO-GSPs with enhanced photothermal conversion properties, allowing rGO-GSPs to be used for sensitive photoacoustic detection and efficient photothermal ablation of tumours in vivo. This study provides a facile approach to prepare colloidal superparticles-graphene hybrid nanostructures and will pave the way toward the design and optimization of photothermal nanomaterials with improved properties for theranostic applications.

Graphitic-phase C3N4 nanosheets as efficient photosensitizers and pH-responsive drug nanocarriers for cancer imaging and therapy.

Graphitic-phase carbon nitride (g-C3N4) nanosheets, the newly emerging two-dimensional (2D) layered nanomaterials, have been demonstrated to be promising bioimaging agents due to their high photoluminescence (PL) quantum yields, good biocompatibility and low toxicity. However, the therapeutic applications of g-C3N4 nanosheets have not been explored until now. In this study, we have proven for the first time that g-C3N4 nanosheets can be used as efficient photosensitizers for photodynamic tumor therapy and as pH-responsive nanocarriers for drug delivery. On one hand, as photosensitizers, g-C3N4 nanosheets are able to generate reactive oxygen species (ROS) and kill cancer cells efficiently under low-intensity light irradiation (20 mW cm-2). On the other hand, as nanocarriers, g-C3N4 nanosheets possess an ultrahigh drug-loading capacity owing to their high surface-to-volume ratio. More importantly, g-C3N4 nanosheets loaded with the anticancer drug doxorubicin (DOX) exhibit a pH-responsive release property which is beneficial for the delivery of DOX into cancer cells for chemotherapy. Furthermore, due to their high PL quantum yields, the fluorescent g-C3N4 nanosheets can enable visualization of the delivery. These findings demonstrated the potential of g-C3N4 nanosheets as low-toxic and biocompatible photosensitizers and pH-responsive drug nanocarriers for biomedical applications.

Multifunctional Fe3O4@polydopamine core-shell nanocomposites for intracellular mRNA detection and imaging-guided photothermal therapy.

Multifunctional nanocomposites have the potential to integrate sensing, diagnostic, and therapeutic functions into a single nanostructure. Herein, we synthesize Fe3O4@polydopamine core-shell nanocomposites (Fe3O4@PDA NCs) through an in situ self-polymerization method. Dopamine, a melanin-like mimic of mussel adhesive proteins, can self-polymerize to form surface-adherent polydopamine (PDA) films onto a wide range of materials including Fe3O4 nanoparticles used here. In such nanocomposites, PDA provides a number of advantages, such as near-infrared absorption, high fluorescence quenching efficiency, and a surface for further functionalization with biomolecules. We demonstrate the ability of the Fe3O4@PDA NCs to act as theranostic agents for intracellular mRNA detection and multimodal imaging-guided photothermal therapy. This work would stimulate interest in the use of PDA as a useful material to construct multifunctional nanocomposites for biomedical applications.

A simple and ultrasensitive electrochemical DNA biosensor based on DNA concatamers.

A simple, ultrasensitive and selective electrochemical DNA biosensor based on DNA concatamers is described, which can detect as low as 100 aM target DNA even in complex samples.