Rosmarinic acid nanomedicine for rheumatoid arthritis therapy: Targeted RONS scavenging and macrophage repolarization.

The infiltration of inflammatory cells, especially macrophages, integrated with the production of reactive oxygen and nitrogen species (RONS) and the release of inflammatory cytokines play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Synergistic combination of RONS scavenging and macrophage repolarization from pro-inflammatory M1 phenotype towards anti-inflammatory M2 phenotype, provides a promising strategy for efficient RA treatment. Herein, this study reported a unique self-assembly strategy to construct distinct rosmarinic acid nanoparticles (RNPs) for efficient RA treatment using the naturally occurring polyphenol-based compound, rosmarinic acid (RosA). The designed RNPs exhibited favorable capability in scavenging RONS and pro-inflammatory cytokines produced by macrophages. Attributing to the widened vascular endothelial-cell gap at inflammation sites, RNPs could target and accumulate at the inflammatory joints of collagen-induced arthritis (CIA) rats for guaranteeing therapeutic effect. In vivo investigation demonstrated that RNPs alleviated the symptoms of RA, including joint swelling, synovial hyperplasia, cartilage degradation, and bone erosion in CIA rats. Additionally, the designed RNPs promoted macrophage polarization from M1 phenotype towards M2 phenotype, resulting in the suppressed progression of RA. Therefore, this research represents the representative paradigm for RA therapy using antioxidative nanomedicine deriving from the natural polyphenol-based compound.

3D-CEUS tracking of injectable chemo-sonodynamic therapy-enabled mop-up of residual renal cell carcinoma after thermal ablation.

Thermal ablation (TA), as a minimally invasive therapeutic technique, has been extensively used to the treatment of solid tumors, such as renal cell carcinoma (RCC), which, unfortunately, still fails to overcome the high risk of local recurrence and distant metastasis since the incomplete ablation cannot be ignored due to various factors such as the indistinguishable tumor margins and limited ablation zone. Herein, we report the injectable thermosensitive hydrogel by confining curcumin (Cur)-loaded hollow mesoporous organosilica nanoparticles (Cur@HMON@gel) which can locate in tumor site more than half a month and mop up the residual RCC under ultrasound (US) irradiation after transforming from colloidal sol status to elastic gel matrix at physiological temperature. Based on the US-triggered accelerated diffusion of the model chemotherapy drug with multi-pharmacologic functions, the sustained and controlled release of Cur has been demonstrated in vitro. Significantly, US is employed as an external energy to trigger Cur, as a sonosensitizer also, to generate reactive oxygen species (ROS) for sonodynamic tumor therapy (SDT) in parallel. Tracking by the three-dimensional contrast-enhanced ultrasound (3D-CEUS) imaging, the typical decreased blood perfusions have been observed since the residual xenograft tumor after incomplete TA were effectively suppressed during the chemo-sonodynamic therapy process. The high in vivo biocompatibility and biodegradability of the multifunctional nanoplatform confined by thermogel provide the potential of their further clinical translation for the solid tumor eradication under the guidance and monitoring of 3D-CEUS.

Engineering Electronic Band Structure of Binary Thermoelectric Nanocatalysts for Augmented Pyrocatalytic Tumor Nanotherapy.

Photothermal therapy (PTT) has emerged as a distinct therapeutic modality owing to its noninvasiveness and spatiotemporal selectivity. However, heat-shock proteins (HSPs) endow tumor cells with resistance to heat-induced apoptosis, severely lowering the therapeutic efficacy of PTT. Here, a high-performance pyroelectric nanocatalyst, Bi13 S18 I2 nanorods (NRs), with prominent pyroelectric conversion and photothermal conversion performance for augmented pyrocatalytic tumor nanotherapy, is developed. Canonical binary compounds are reconstructed by inserting a third biocompatible agent, thus facilitating the formation of Bi13 S18 I2 NRs with enhanced pyrocatalytic conversion efficiency. Under 808 nm laser irradiation, Bi13 S18 I2 NRs induce a conspicuous temperature elevation for photonic hyperthermia. In particular, Bi13 S18 I2 NRs harvest pyrocatalytic energy from the heating and cooling alterations to produce abundant reactive oxygen species, which results in the depletion of HSPs and hence the reduction of thermoresistance of tumor cells, thereby significantly augmenting the therapeutic efficacy of photothermal tumor hyperthermia. By synergizing the pyroelectric dynamic therapy with PTT, tumor suppression with a significant tumor inhibition rate of 97.2% is achieved after intravenous administration of Bi13 S18 I2 NRs and subsequent exposure to an 808 nm laser. This work opens an avenue for the design of high-performance pyroelectric nanocatalysts by reconstructing canonical binary compounds for therapeutic applications in biocatalytic nanomedicine.

Engineering Oxygen-Irrelevant Radical Nanogenerator for Hypoxia-Independent Magnetothermodynamic Tumor Nanotherapy.

Tumor hypoxia substantially lowers the treatment efficacy of oxygen-relevant therapeutic modalities because the production of reactive oxygen species in oxygen-relevant anticancer modalities is highly dependent on oxygen level in tumor tissues. Here a distinctive magnetothermodynamic anticancer strategy is developed that takes the advantage of oxygen-irrelevant free radicals produced from magnetothermal decomposable initiators for inducing cancer-cell apoptosis in vitro and tumor suppression in vivo. Free-radical nanogenerator is constructed through in situ engineering of a mesoporous silica coating on the surface of superparamagnetic Mn and Co-doped nanoparticles (MnFe2 O4 @CoFe2 O4 , denoted as Mag) toward multifunctionality, where mesoporous structure provides reservoirs for efficient loading of initiators and the Mag core serves as in situ heat source under alternating magnetic field (AMF) actuation. Upon exposure to an exogenous AMF, the magnetic hyperthermia effect of superparamagnetic core lead to the rapid decomposition of the loaded/delivered initiators (AIPH) to produce oxygen-irrelevant free radicals. Both the magnetothermal effect and generation of toxic free radicals under AMF actuation are synergistically effective in promoting cancer-cell death and tumor suppression in the hypoxic tumor microenvironment. The prominent therapeutic efficacy of this radical nanogenerator represents an intriguing paradigm of oxygen-irrelevant nanoplatform for AMF-initiated synergistic cancer treatment.

Hypoxia-Irrelevant Photonic Thermodynamic Cancer Nanomedicine.

The hypoxic tumor microenvironment severely lowers the therapeutic efficacy of oxygen-dependent anticancer modalities because tumor hypoxia hinders the generation of toxic reactive oxygen species. Here we report a thermodynamic cancer-therapeutic modality that employs oxygen-irrelevant free radicals generated from thermo-labile initiators for inducing cancer cell death. A free radical nanogenerator was engineered via direct growth of mesoporous silica layer onto the surface of two-dimensional Nb2C MXene nanosheets toward multifunctionality, where the mesopore provided the reservoirs for initiators and the MXene core acted as the photonic-thermal trigger at the near-infrared-II biowindow (NIR-II). Upon illumination by a 1064 nm NIR-II laser, the photothermal-conversion effect of Nb2C MXene induced the fast release and quick decomposition of the encapsulated initiators (AIPH) to produce free radicals, which promoted cancer cell apoptosis in both normoxic and hypoxic microenvironment. Systematic in vitro and in vivo evaluations have demonstrated the synergistic-therapeutic outcome of this intriguing photonic nanoplatform-enabled thermodynamic cancer therapy for completely eradicating the 4T1 tumors without recurrence by NIR-II laser irradiation. This work pioneers the thermodynamic therapy for oxygen-independent cancer treatment by photonic triggering at the NIR-II biowindow.

Fast-Clearable Nanocarriers Conducting Chemo/Photothermal Combination Therapy to Inhibit Recurrence of Malignant Tumors.

Inhomogeneous heating by photothermal therapy (PTT) during cancer treatment often results in the recurrence of tumors. Thus, integrating PTT with chemotherapy (CHT) may provide a complementary treatment for enhanced therapeutic efficiency. Herein, this study develops a hollow structured polymer-silica nanohybrid (HPSN) as a nanocarrier to simultaneously deliver the anticancer drug paclitaxel and photothermal agent palladium phthalocyanine to tumors through enhanced permeation and the retention effect. A combinational CHT/PTT therapy on mice bearing aggressive tumor grafts is conducted. The highly malignant tumor model, which recurs after sole treatment of PTT, can be eradicated by the combined CHT/PTT treatment. In addition, most of the off-targeted HPSN nanocarriers can be excreted through a hepatobiliary pathway in about 10 d. Serology results show that the fast-clearable HPSN can significantly reduce the side effect of the loaded paclitaxel drug. The present work provides an alternative approach for combinational cancer treatment with high therapeutic efficiency.