Ultrasound-Remote Selected Activation Mitophagy for Precise Treatment of Rheumatoid Arthritis by Two-Dimensional Piezoelectric Nanosheets.

Excess reactive oxygen species (ROS) produced by abnormal mitochondria is one of the critical triggers of rheumatoid arthritis (RA). Existing nanocatalytic therapies can only catalyze the breakdown of ROS but cannot address the root cause of ROS production, i.e., abnormal mitochondria. Here, we designed an ultrasound (US) piezoelectric catalytic therapy, which can induce mitophagy in a spatiotemporally controlled manner to treat RA. The prepared two-dimensional piezoelectric nanosheets (NSs) Fe/BiOCl with US catalytic activity can efficiently generate electrons under US stimulation to meet the purpose of consuming H+ in the outer mitochondrial membrane and disturbing the H+ supply in the mitochondrial matrix. This causes depolarization of the mitochondrial membrane potential (MMP), triggering the autophagy of mitochondria in regions of inflammation to eliminate the source of ROS regeneration. Analysis of cellular and RA model-related experiments showed that piezoelectric US-catalyzed therapy involving Fe/BiOCl NSs alleviated RA by inducing mitophagy. This provides an explanation of the mechanism for piezoelectric US catalytic therapy and suggests promising strategies for biomedical applications of US piezoelectric materials.

Bionic Dormant Body of Timed Wake-Up for Bacteriotherapy in Vivo.

The microorganism has become a promising therapeutic tool for many diseases because it is a kind of cell factory that can efficiently synthesize a variety of bioactive substances. However, the metabolic destiny of microorganisms is difficult to predict in vivo. Here, a timing bionic dormant body with programmable destiny is reported, which can predict the metabolic time and location of microorganisms in vivo and can prevent it from being damaged by the complex biological environment in vivo. Taking the complex digestive system as an example, the bionic dormant body exists in the upper digestive tract as a nonmetabolic dormant body after oral administration and will be awakened to synthesize bioactive substances about 2 h after reaching the intestine. Compared with oral microorganisms alone, the bioavailability of the biomimetic dormant body in the intestine is almost 3.5 times higher. The utilization rate of the oral bionic dormant body to synthesize drugs is 2.28 times higher than oral drugs. We demonstrated the significant efficacies of treatment using Parkinson's disease (PD) mice by dormant body capable of timed neurotransmitter production after oral delivery. The timed bionic dormant body with programmable destiny may provide an effective technology to generate advanced microbial therapies for the treatment of various diseases.

Nanoarmour-shielded single-cell factory for bacteriotherapy of Parkinson's disease.

Cell-based therapy for Parkinson's disease (PD) is a novel and promising approach in recent years. However, exogenous cells are easy to be captured and destroyed by the harsh environment in vivo, so their application prospects have been severely limited. Here, a facile yet versatile approach for decorating individual living cells with nano-armor coatings is reported. By simply self-assembly with liposome under a cyto-compatible condition, the lipid bimolecular coating on the surface of each cell acts as armor to effectively protect it from the attack and destruction of strong acids and digestive enzymes during the oral treatment of PD. Our results demonstrated that the liposome coated B. adolescentis (LCB) could significantly improve the colonization rate in the intestinal tract. LCB, as a living cell factory, can self-regulate to produce a constant concentration of γ-aminobutyric acid and maintain a longer half-life for the treatment of PD. Then, we also explored the specific mechanism of LCB to improve the behavior of murine models of PD, including abating inflammatory effects, reducing neuronal apoptosis, regulating the activity of dopaminergic neurons and microglia. The simple nano-armor shielded single-cell factory can produce neurotransmitters-like drugs on demand in vivo, introducing novel strategies of integration of producing and using to the research of drug delivery field.

NIR-Responsive Spatiotemporally Controlled Cyanobacteria Micro-Nanodevice for Intensity-Modulated Chemotherapeutics in Rheumatoid Arthritis.

The expression of hypoxia-inducible factor-1α (HIF-1α) is upregulated in hypoxic environments at the lesions of rheumatoid arthritis (RA), which promoted the polarization of proinflammatory M1 macrophages and inhibited the differentiation of anti-inflammatory M2 to deteriorate synovial inflammation. Since oxygen scarcity at the joints causes an imbalance of macrophages M1 and M2, herein, we designed a cyanobacteria micro-nanodevice that can be spatiotemporally controlled in vivo to continuously producing oxygen in the RA joints for the downregulation of the expression of HIF-1α, thereby reducing the amounts of M1 macrophages and inducing the polarization of M2 macrophages for chemically sensitized RA treatment. The forthputting of temperature-sensitive hydrogel guaranteed the safety of cyanobacteria micro-nanodevice in vivo. Furthermore, the oxygen produced by cyanobacteria micro-nanodevice in a sustained manner enhanced the therapeutic effect of the antirheumatic drug methotrexate (MTX) and discouraged inflammation and bone erosion at RA. This study provided a new approach for the RA treatment of spatiotemporal-controlled release of oxygen in vitro.