Spatially Asymmetric Nanoparticles for Boosting Ferroptosis in Tumor Therapy.

Despite its effectiveness in eliminating cancer cells, ferroptosis is hindered by the high natural antioxidant glutathione (GSH) levels in the tumor microenvironment. Herein, we developed a spatially asymmetric nanoparticle, Fe3O4@DMS&PDA@MnO2-SRF, for enhanced ferroptosis. It consists of two subunits: Fe3O4 nanoparticles coated with dendritic mesoporous silica (DMS) and PDA@MnO2 (PDA: polydopamine) loaded with sorafenib (SRF). The spatial isolation of the Fe3O4@DMS and PDA@MnO2-SRF subunits enhances the synergistic effect between the GSH-scavengers and ferroptosis-related components. First, the increased exposure of the Fe3O4 subunit enhances the Fenton reaction, leading to increased production of reactive oxygen species. Furthermore, the PDA@MnO2-SRF subunit effectively depletes GSH, thereby inducing ferroptosis by the inactivation of glutathione-dependent peroxidases 4. Moreover, the SRF blocks Xc- transport in tumor cells, augmenting GSH depletion capabilities. The dual GSH depletion of the Fe3O4@DMS&PDA@MnO2-SRF significantly weakens the antioxidative system, boosting the chemodynamic performance and leading to increased ferroptosis of tumor cells.

Fluorine Doping Mediated Epitaxial Growth of NaREF4 on TiO2 for Boosting NIR Light Utilization in Bioimaging and Photodynamic Therapy.

By integrating TiO2 with rare earth upconversion nanocrystals (NaREF4), efficient energy transfer can be achieved between the two subunits under near-infrared (NIR) excitation, which hold tremendous potential in the fields of photocatalysis, photodynamic therapy (PDT), etc. However, in the previous studies, the combination of TiO2 with NaREF4 is a non-epitaxial random blending mode, resulting in a diminished energy transfer efficiency between the NaREF4 and TiO2. Herein, we present a fluorine doping-mediated epitaxial growth strategy for the synthesis of TiO2-NaREF4 heteronanocrystals (HNCs). Due to the epitaxial growth connection, NaREF4 can transfer energy through phonon-assisted pathway to TiO2, which is more efficient than the traditional indirect secondary photon excitation. Additionally, F doping brings oxygen vacancies in the TiO2 subunit, which further introduces new impurity energy levels in the intrinsic band gap of TiO2 subunit, and facilitates the energy transfer through phonon-assisted method from NaREF4 to TiO2. As a proof of concept, TiO2-NaGdF4 : Yb,Tm@NaYF4@NaGdF4 : Nd@NaYF4 HNCs were rationally constructed. Taking advantage of the dual-model up- and downconversion luminescence of the delicately designed multi-shell structured NaREF4 subunit, highly efficient photo-response capability of the F-doped TiO2 subunit and the efficient phonon-assisted energy transfer between them, the prepared HNCs provide a distinctive nanoplatform for bioimaging-guided NIR-triggered PDT.

Surface curvature-induced oriented assembly of sushi-like Janus therapeutic nanoplatform for combined chemodynamic therapy.

BACKGROUND: Chemodynamic therapy (CDT) based on Fenton/Fenton-like reaction has emerged as a promising cancer treatment strategy. Yet, the strong anti-oxidation property of tumor microenvironment (TME) caused by endogenous glutathione (GSH) still severely impedes the effectiveness of CDT. Traditional CDT nanoplatforms based on core@shell structure possess inherent interference of different subunits, thus hindering the overall therapeutic efficiency. Consequently, it is urgent to construct a novel structure with isolated functional units and GSH depletion capability to achieve desirable combined CDT therapeutic efficiency. RESULTS: Herein, a surface curvature-induced oriented assembly strategy is proposed to synthesize a sushi-like novel Janus therapeutic nanoplatform which is composed of two functional units, a FeOOH nanospindle serving as CDT subunit and a mSiO2 nanorod serving as drug-loading subunit. The FeOOH CDT subunit is half covered by mSiO2 nanorod along its long axis, forming sushi-like structure. The FeOOH nanospindle is about 400 nm in length and 50 nm in diameter, and the mSiO2 nanorod is about 550 nm in length and 100 nm in diameter. The length and diameter of mSiO2 subunit can be tuned in a wide range while maintaining the sushi-like Janus structure, which is attributed to a Gibbs-free-energy-dominating surface curvature-induced oriented assembly process. In this Janus therapeutic nanoplatform, Fe3+ of FeOOH is firstly reduced to Fe2+ by endogenous GSH, the as-generated Fe2+ then effectively catalyzes overexpressed H2O2 in TME into highly lethal ·OH to achieve efficient CDT. The doxorubicin (DOX) loaded in the mSiO2 subunit can be released to achieve combined chemotherapy. Taking advantage of Fe3+-related GSH depletion, Fe2+-related enhanced ·OH generation, and DOX-induced chemotherapy, the as-synthesized nanoplatform possesses excellent therapeutic efficiency, in vitro eliminating efficiency of tumor cells is as high as ~ 87%. In vivo experiments also show the efficient inhibition of tumor, verifying the synthesized sushi-like Janus nanoparticles as a promising therapeutic nanoplatform. CONCLUSIONS: In general, our work provides a successful paradigm of constructing novel therapeutic nanoplatform to achieve efficient tumor inhibition.

Black Titania Janus Mesoporous Nanomotor for Enhanced Tumor Penetration and Near-Infrared Light-Triggered Photodynamic Therapy.

Thanks to their excellent photoelectric characteristics to generate cytotoxic reactive oxygen species (ROS) under the light-activation process, TiO2 nanomaterials have shown significant potential in photodynamic therapy (PDT) for solid tumors. Nevertheless, the limited penetration depth of TiO2-based photosensitizers and excitation sources (UV/visible light) for PDT remains a formidable challenge when confronted with complex tumor microenvironments (TMEs). Here, we present a H2O2-driven black TiO2 mesoporous nanomotor with near-infrared (NIR) light absorption capability and autonomous navigation ability, which effectively enhances solid tumor penetration in NIR light-triggered PDT. The nanomotor was rationally designed and fabricated based on the Janus mesoporous nanostructure, which consists of a NIR light-responsive black TiO2 nanosphere and an enzyme-modified periodic mesoporous organosilica (PMO) nanorod that wraps around the TiO2 nanosphere. The overexpressed H2O2 can drive the nanomotor in the TME under catalysis of catalase in the PMO domain. By precisely controlling the ratio of TiO2 and PMO compartments in the Janus nanostructure, TiO2&PMO nanomotors can achieve optimal self-propulsive directionality and velocity, enhancing cellular uptake and facilitating deep tumor penetration. Additionally, by the decomposition of endogenous H2O2 within solid tumors, these nanomotors can continuously supply oxygen to enable highly efficient ROS production under the NIR photocatalysis of black TiO2, leading to intensified PDT effects and effective tumor inhibition.

Site-specific anisotropic assembly of amorphous mesoporous subunits on crystalline metal-organic framework.

As an important branch of anisotropic nanohybrids (ANHs) with multiple surfaces and functions, the porous ANHs (p-ANHs) have attracted extensive attentions because of the unique characteristics of high surface area, tunable pore structures and controllable framework compositions, etc. However, due to the large surface-chemistry and lattice mismatches between the crystalline and amorphous porous nanomaterials, the site-specific anisotropic assembly of amorphous subunits on crystalline host is challenging. Here, we report a selective occupation strategy to achieve site-specific anisotropic growth of amorphous mesoporous subunits on crystalline metal-organic framework (MOF). The amorphous polydopamine (mPDA) building blocks can be controllably grown on the {100} (type 1) or {110} (type 2) facets of crystalline ZIF-8 to form the binary super-structured p-ANHs. Based on the secondary epitaxial growth of tertiary MOF building blocks on type 1 and 2 nanostructures, the ternary p-ANHs with controllable compositions and architectures are also rationally synthesized (type 3 and 4). These intricate and unprecedented superstructures provide a good platform for the construction of nanocomposites with multiple functionalities and understanding of the structure-property-function relationships.

Multifunctional Janus Nanoplatform for Efficiently Synergistic Theranostics of Rheumatoid Arthritis.

Progress has been made in the application of nanomedicine in rheumatoid arthritis (RA) treatment. However, the whole process of monitoring and treatment of RA remains a formidable challenge due to the complexity of the chronic autoimmune disease. In this study, we develop a Janus nanoplatform (denoted as Janus-CPS) composed of CeO2-Pt nanozyme subunit on one side and periodic mesoporous organosilica (PMO) subunit on another side for simultaneous early diagnosis and synergistic therapy of RA. The Janus nanostructure, which enables more active sites to be exposed, enhances the reactive oxygen species scavenging capability of CeO2-Pt nanozyme subunit as compared to their core-shell counterpart. Furthermore, micheliolide (MCL), an extracted compound from natural plants with anti-osteoclastogenesis effects, is loaded into the mesopores of PMO subunit to synergize with the anti-inflammation effect of nanozymes for efficient RA treatment, which has been demonstrated by in vitro cellular experiments and in vivo collagen-induced arthritis (CIA) model. In addition, by taking advantage of the second near-infrared window (NIR-II) fluorescent imaging, indocyanine green (ICG)-loaded Janus-CPS exhibits desirable effectiveness in detecting RA lesions at a very early stage. It is anticipated that such a Janus nanoplatform may offer an alternative strategy of functional integration for versatile theranostics.

Versatile synthesis of dendritic mesoporous rare earth-based nanoparticles.

Rare earth-based nanomaterials that have abundant optical, magnetic, and catalytic characteristics have many applications. The controllable introduction of mesoporous channels can further enhance its performance, such as exposing more active sites of rare earth and improving the loading capacity, yet remains a challenge. Here, we report a universal viscosity-mediated assembly strategy and successfully endowed rare earth-based nanoparticles with central divergent dendritic mesopores. More than 40 kinds of dendritic mesoporous rare earth-based (DM-REX) nanoparticles with desired composition (single or multiple rare earth elements, high-entropy compounds, etc.), particle diameter (80 to 500 nanometers), pore size (3 to 20 nanometers), phase (amorphous hydroxides, crystalline oxides, and fluorides), and architecture were synthesized. Theoretically, a DM-REX nanoparticle library with 393,213 kinds of possible combinations can be constructed on the basis of this versatile method, which provides a very broad platform for the application of rare earth-based nanomaterials with rational designed functions and structures.