Nature nanotechnology最新文献

Intra-articular RNA therapeutics have shown promise in osteoarthritis (OA); however, maximizing their efficacy requires targeted delivery to degenerating cartilage within focal lesions. As OA progresses, cartilage degeneration worsens, necessitating disease-responsive targeting with enhanced delivery in advanced stages. Here we develop an anionic nanoparticle (NP) strategy for targeting glycosaminoglycan loss, a hallmark of OA's progression that reduces cartilage's negative charge. These NPs selectively diffuse and accumulate into matrix regions inversely correlated with glycosaminoglycan content owing to reduced electrostatic repulsion, a strategy we term 'matrix inverse targeting' (MINT). In a mouse model of OA, intra-articular delivery of luciferase messenger RNA-loaded MINT NPs demonstrated disease-severity-responsive expression. Using this strategy, we delivered ghrelin mRNA, as ghrelin has shown chondroprotection properties previously. Ghrelin mRNA-loaded MINT NPs reduced cartilage degeneration, subchondral bone thickening and nociceptive pain. Our findings highlight the potential of ghrelin mRNA delivery as a disease-modifying therapy for OA and the platform's potential for lesion-targeted RNA delivery responsive to disease severity.

Control of charge and heat transport is essential for computing and thermal management technologies. Recent work with superconducting materials has shown rectified electrical supercurrents near liquid helium temperatures. However, despite large theoretical interest and expected impact on quantum technologies, no experiments have demonstrated control of nanoscale radiative heat currents at cryogenic temperatures. Here we study photon-mediated thermal transport in nanogaps between niobium and gold. Using novel scanning calorimetric probes and nanofabricated devices, we reveal a ~20-fold suppression of radiative heat transport, when niobium transitions from the metallic to the superconducting state. Taking advantage of this effect, we also demonstrate a niobium-based cryogenic thermal diode with a heat rectification ratio of 70%. The experimental techniques and advances presented here will enable studying nanoscale thermal transport in quantum materials and advancing thermal management of superconducting devices.

Despite the considerable success of clinically approved immune-based therapies for treating advanced melanoma, a significant fraction of patients are not responsive owing to mechanisms engaged by the tumour to evade the immune system. Here we report the surprising finding that a clinically validated and tunable self-therapeutic ultrasmall silica nanoparticle prolongs survival in a highly resistant melanoma model in combination with interleukin-6 and PD-L1 inhibition through activation of the stimulator of interferon genes/interleukin-6/PD-L1 axis and reprogramming of the tumour microenvironment towards a pro-inflammatory phenotype. In a murine model, induction of significant cytotoxic and antitumour inflammatory responses leads to differential activation of immune cell populations in a CD8-dependent manner via type I/II interferon pathways after systemic particle injection. Importantly, these immunostimulatory responses accompany significant reductions in cell populations and receptors driving suppressive activities. Mechanistic insights highlight the potential clinical utility of this platform to maximize antitumour immunity and efficacy by subverting suppressive components in the tumour microenvironment.

Osteoarthritis (OA) affects a large population worldwide, causing chronic pain, functional decline, and increased personal and societal medical costs. A major challenge in developing disease-modifying OA drugs (DMOADs) is the inefficient delivery to diseased chondrocytes. Here we synthesize a viral glycoprotein-mimicking peptide (CMP) containing a type II collagen-adhesive motif and a matrix metalloproteinase-13-activated cell-penetrating peptide sequence. The CMP peptide was conjugated to small-sized micelles loaded with the model drug IOX4, enabling the micelles to adhere to cartilage and chondrocyte surfaces through collagen binding and achieve proteinase-induced selective uptake by diseased chondrocytes. In an OA mouse model, our micelles demonstrated prolonged joint retention and exhibited a higher uptake by diseased chondrocytes compared with unmodified micelles and normal chondrocytes, respectively. In both OA mice and a clinically relevant OA sheep model, our system maintained metabolic homeostasis in cartilage, attenuating OA pathological changes and improving symptoms without causing additional toxicity. These findings suggest that our nanoformulation is a promising DMOAD candidate and provides an efficient delivery strategy for other potential DMOADs targeting intracellular sites of diseased chondrocytes.