Leo Kit Cheung Lee

Huntington's disease (HD) is a severe neurodegenerative disorder that causes motor impairment and ultimately death. Yet, safe and effective disease-modifying treatments of HD are scarce, and delivery to the HD brain is challenging. Here, we present a small, ∼11 nm polyethylene glycol-coated gold nanoparticle (NP) for brain delivery and treating HD in R6/2 mice. Upon intravenous injection, this NP crosses brain barriers, preferentially accumulates in the brain of R6/2 mice than healthy littermates without pronounced liver or kidney sequestration, diffuses to the cortex and striatum, and enters neurons and microglia. Devoid of known chemical or biological drugs, this NP improves motor deficit as effectively as tetrabenazine (standard therapy for symptomatic relief) and prolongs survival, without long-term brain retention or systemic toxicity. This NP activates the oxidative phosphorylation pathway, blocks p38α mitogen-activated protein kinase phosphorylation and pyruvate dehydrogenase kinase 1 activity, and inhibits pyroptosis. Our data offer molecular insights into gold nanomedicines against neurodegenerative diseases.

Acute respiratory distress syndrome (ARDS) is a severe lung inflammatory condition with a global mortality rate of ≈40%. Yet, many treatments are invasive and non‐specific for ARDS, require days to yield efficacy, or suffer from systemic side effects and limited delivery to the lung epithelium, a key protective structure against ARDS. A disease‐driven, non‐invasive nanomedicine is reported for ARDS. Initially, the transient, sequential activation of L–SIGN and ACE2 receptors on the lung epithelium induced by ARDS onset in two hamster models (lipopolysaccharides and hydrochloric acid induction) is discovered. With this bioinspiration, an inhalable, Spike receptor–binding domain–conjugated gold nanoparticle is designed for tissue‐wide delivery to ARDS lungs, with its specific entry to epithelial cells mediated additively by both receptors. The gold core naturally blocks p38α mitogen‐activated protein kinase and polo‐like kinase 3 without chemical or biological drugs. Notably, this nanoparticle reduces lung inflammation, oxidative stress, and tissue injury more effectively than steroid after six total hours of inhalation, improves lung function, and does not lead to systemic retention or toxicity 1–year post–treatment. Inhalable, epithelium–targeting nanomedicines may offer safe and effective treatments for lung diseases.

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio–nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-κB pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (∼1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.

DNA nanostructures are attractive gene carriers for nanomedicine applications, yet their delivery to the nucleus remains inefficient. We present the application of extracellular mechanical stimuli to activate cellular mechanotransduction for boosting the intranuclear delivery of DNA nanostructures. Treating mammalian cells with polythymidine-rich spherical nucleic acids (poly(T) SNAs) under gentle compression by a single coverslip leads to up to ∼50% nuclear accumulation without severe endosomal entrapment, cytotoxicity, or long-term membrane damage; no chemical modification or transfection reagent is needed. Gentle compression activates Rho-ROCK mechanotransduction and causes nuclear translocation of YAP. Joint compression and treatment with poly(T) oligonucleotides upregulate genes linked to myosin, actin filament, and nuclear import. In turn, Rho-ROCK, myosin, and importin mediate the nuclear entry of poly(T) SNAs. Treatment of endothelioma cells with poly(T) SNAs bearing antisense oligonucleotides under compression inhibits an intranuclear oncogene. Our data should inspire the marriage of DNA nanotechnology and cellular biomechanics for intranuclear applications.

We present a self-therapeutic nanoparticle for topical delivery to epidermal keratinocytes to prevent and treat psoriasis. Devoid of known chemical or biological antipsoriatic drugs, this sub−15 nm nanoparticle contains a 3 nm gold core and a shell of 1000 Da polyethylene glycol strands modified with 30% octadecyl chains. When it is applied to imiquimod-induced psoriasis mice without an excipient, the nanoparticle can cross the stratum corneum and preferentially enter keratinocytes. Applying the nanoparticles concurrently with imiquimod prevents psoriasis and downregulates genes that are enriched in the downstream of the interleukin-17 signaling pathway and linked to epidermis hyperproliferation and inflammation. Applying the nanoparticles after psoriasis is established treats the psoriatic skin as effectively as standard steroid and vitamin D analog-based therapy but without hair loss and skin wrinkling. The nanoparticles do not accumulate in major organs or induce long-term toxicity. Our nanoparticle offers a simple, safe, and effective alternative for treating psoriasis.

Polyglutamine (polyQ) diseases, such as Huntington’s disease and several types of spinocerebellar ataxias, are dominantly inherited progressive neurodegenerative disorders and characterized by the presence of expanded CAG trinucleotide repeats in the respective disease locus of the patient genomes. Patients with polyQ diseases currently need to rely on symptom-relieving treatments because disease-modifying therapeutic interventions remain scarce. Many disease-modifying therapeutic agents are now under clinical testing for treating polyQ diseases, but their delivery to the brain is often too invasive (e.g., intracranial injection) or inefficient, owing to in vivo degradation and clearance by physiological barriers (e.g., oral and intravenous administration). Nanoparticles provide a feasible solution for improving drug delivery to the brain, as evidenced by an increasing number of preclinical studies that document the efficacy of nanomedicines for polyQ diseases over the past 5–6 years. In this review, we present the pathogenic mechanisms of polyQ diseases, the common animal models of polyQ diseases for evaluating the efficacy of nanomedicines, and the common administration routes for delivering nanoparticles to the brain. Next, we summarize the recent preclinical applications of nanomedicines for treating polyQ diseases and improving neurological conditions in vivo, placing emphasis on antisense oligonucleotides, small peptide inhibitors, and small molecules as the disease-modifying agents. We conclude with our perspectives of the burgeoning field of “nanomedicines for polyQ diseases”, including the use of inorganic nanoparticles and potential drugs as next-generation nanomedicines, development of higher-order animal models of polyQ diseases, and importance of “brain-nano” interactions.

Concerns over the health risks associated with airborne exposure to ultrafine particles [PM0.1, or nanoparticles (NPs)] call for a comprehensive understanding in the interactions of inhaled NPs along their respiratory journey. We prepare a collection of polyethylene glycol-coated gold nanoparticles that bear defined functional groups commonly identified in atmospheric particulates ([email protected] NPs, where X = OCH₃, COOH, NH₂, OH or C₁₂H₂₅). Regardless of functional group, these ~50 nm NPs remain colloidally stable following aerosolization and incubation in bronchoalveolar lavage fluid (BALF), without pronouncedly crossing the air-blood-barrier. The type of BALF proteins adhered onto the NPs is similar, but the composition of protein corona depends on functional group. By subjecting Balb/c mice to inhalation of [email protected] NPs for 6 h, we demonstrate that the intrapulmonary distribution of NPs among the various types of cells (both found in BALF and isolated from the lavaged lung) and the acute inflammatory responses induced by inhalation are sensitive to the functional group of NPs and post-inhalation period (0 h, 24 h, and 48 h). By evaluating the pairwise correlations between the three variables of “lung-nano” interactions (protein corona, intrapulmonary cellular-level distribution, and inflammatory response), we reveal strong statistical correlations between the (1) fractions of albumin or carbonyl reductase bound to NPs, (2) associations of inhaled NPs to neutrophils in BALF or macrophages in the lavaged lung, and (3) level of total proteins in BALF. Our results provide insights into the effect of functional group on lung-nano interactions and health risks associated with inhalation of PM0.1.