Wanxin Huang

Abnormal mechanical loading often leads to the progressive degradation of cartilage and causes osteoarthritis (OA). Although multiple mechanoresponsive strategies based on biomaterials have been designed to restore healthy cartilage microenvironments, methods to remotely control the on-demand mechanical forces for cartilage repair pose significant challenges. Here, a magneto-mechanically controlled mesenchymal stem cell (MSC) platform, based on the integration of intercellular mechanical communication and intracellular mechanosignaling processes, is developed for OA treatment. MSCs loaded with antioxidative melanin@Fe3O4 magnetic nanoparticles (Magcells) rapidly assemble into highly ordered cell clusters with enhanced cell–cell communication under a time-varying magnetic field, which enables long-term retention and differentiation of Magcells in the articular cavity. Subsequently, via mimicking the gait cycle, chondrogenesis can be further enhanced by the dynamic activation of mechanical signaling processes in Magcells. This sophisticated magneto-mechanical actuation strategy provides a paradigm for developing mechano-therapeutics to repair cartilage in OA treatment.

Abstract Targeting ferroptosis has attracted exponential attention to eradicate cancer cells with high iron‐dependent growth. Increasing the level of intracellular labile iron pool via small molecules and iron‐containing nanomaterials is an effective approach to induce ferroptosis but often faces insufficient efficacy due to the fast drug metabolism and toxicity issues on normal tissues. Therefore, developing a long‐acting and selective approach to regulate ferroptosis is highly demanded in cancer treatment. Herein, a lysosome‐targeted magnetic nanotorquer (T7‐MNT) is proposed as the mechanical tool to dynamically induce the endogenous Fe 2+ pool outbreak for ferroptosis of breast cancer. T7‐MNTs target lysosomes via the transferrin receptor‐mediated endocytosis in breast cancer cells. Under the programmed rotating magnetic field, T7‐MNTs generate torques to trigger endogenous Fe 2+ release by disrupting the lysosomal membrane. This magneto‐mechanical manipulation can induce oxidative damage and antioxidant defense imbalance to boost frequency‐ and time‐dependent lipid peroxidization. Importantly, in vivo studies show that T7‐MNTs can efficiently trigger ferroptosis under the magnetic field and play as a long‐acting physical inducer to boost ferrotherapy efficacy in combination with RSL3. It is anticipated that this dynamic targeted strategy can be coupled with current ferroptosis inducers to achieve enhanced efficacy and inspire the design of mechanical‐based ferroptosis inducers for cancer treatment.

Magnetic nanorobots are emerging players in thrombolytic therapy due to their noninvasive remote actuation and drug loading capabilities. Although the nanorobots with a size under 100 nm are ideal to apply in microvascular systems, the propulsion performance of nanorobots is inevitably compromised due to the limited response to magnetic fields. Here, we demonstrate a nattokinase-loaded magnetic vortex nanorobot (NK-MNR) with an average size around 70 nm and high saturation magnetization for mechanical propelling and thermal responsive thrombolysis under a magnetic field with dual frequencies. The nanorobots are stable in suspension and undergo the magneto-steered assembly into chain-like NK-MNRs, which are regulated to generate magnetic forces to mechanically damage and penetrate the thrombus by the low-frequency rotating magnetic field. Synergistically, enhanced magnetic hyperthermia is triggered by an alternating magnetic field of high frequency, enabling heat-induced NK release and fibrinolysis. In this dual frequency-regulated magnetothrombolysis (fRMT) strategy, nanorobots collaborate under the dual magnetic energy conversion model to achieve the vasculature recanalization rate of 81.0% in thrombotic mice. Overall, the nanorobot with the special magnetic vortex property and multimodel controls is a promising nanoplatform for in vivo focalized microvascular thrombolysis.

Natural killer (NK) cells engage target cells via the immunological synapse (IS), where inhibitory and activating signals determine whether NK cell cytotoxicity is suppressed or activated. We previously reported that cancer cells can rapidly remodel their actin cytoskeleton upon NK cell engagement, leading to F-actin accumulation at the synapse. Here, we show that this process inhibits NK cell activation as indicated by impaired MTOC and lytic granule polarization. Exploring the underlying mechanism, we demonstrate that actin remodeling drives the recruitment of inhibitory ligands, such as HLA-A, -B, and -C, to the synapse. Disrupting HLA interaction with their cognate inhibitory receptors KIRs restores NK cell activation. Using NK cells expressing inhibitory KIR receptors, matched or unmatched to HLA molecules on cancer cells, we show that synaptic F-actin accumulation and matching KIR-HLA interactions jointly suppress NK cell cytotoxicity. Our findings reveal an immune evasion strategy in which cancer cells impair NK cell activation by altering synaptic signaling through actin cytoskeleton-driven recruitment of inhibitory signals to the IS.