Targeted NAD repletion via biomimetic nanoparticle enables simultaneous management of intimal hyperplasia and accelerated re-endothelialization: A proof-of-concept study toward next-generation of endothelium-protective, anti-restenotic therapy.

Endovascular interventions often fail due to restenosis, primarily caused by smooth muscle cell (SMC) proliferation, leading to intimal hyperplasia (IH). Current strategies to prevent restenosis are far from perfect and impose significant collateral damage on the fragile endothelial cell (EC), causing profound thrombotic risks. Nicotinamide adenine dinucleotide (NAD) is a co-enzyme and signaling substrate implicated in redox and metabolic homeostasis, with a pleiotropic role in protecting against cardiovascular diseases.

Photodynamic Therapy for Atherosclerosis: Past, Present, and Future.

This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation.

Multimodal nanoimmunotherapy engages neutrophils to eliminate Staphylococcus aureus infections.

The increasing prevalence of antimicrobial resistance in Staphylococcus aureus necessitates alternative therapeutic approaches. Neutrophils play a crucial role in the fight against S. aureus but suffer from deficiencies in function leading to increased infection.

Non-viral approaches for gene therapy and therapeutic genome editing across the blood-brain barrier.

The success of brain-targeted gene therapy and therapeutic genome editing hinges on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which presents a significant challenge in the development of treatments for central nervous system disorders. This is particularly the case for nucleic acids and genome editors that are naturally excluded by the BBB and have poor chemical stability in the bloodstream and poor cellular uptake capability, thereby requiring judiciously designed nanovectors administered systemically for intracellular delivery to brain cells such as neurons. To overcome this obstacle, various strategies for bypassing the BBB have been developed in recent years to deliver biologics to the brain via intravenous administration using non-viral vectors.

Neointima abating and endothelium preserving - An adventitia-localized nanoformulation to inhibit the epigenetic writer DOT1L.

Open vascular reconstructions such as bypass are common treatments for cardiovascular disease. Unfortunately, neointimal hyperplasia (IH) follows, leading to treatment failure for which there is no approved therapy. Here we combined the strengths of tailoring nanoplatforms for open vascular reconstructions and targeting new epigenetic mechanisms.

Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases.

Guanidinium-Rich Lipopeptide-Based Nanoparticle Enables Efficient Gene Editing in Skeletal Muscles.

Genome editing mediated by the CRISPR-Cas system holds great promise for the treatment of genetic diseases. However, safe and efficient in vivo delivery of CRISPR genome editing machinery remains a challenge. Here, we report a lipopeptide-based nanoparticle (LNP) that can efficiently deliver the CRISPR Cas9/sgRNA ribonucleoprotein (RNP) and enable efficient genome editing both and .

Efficient in vivo neuronal genome editing in the mouse brain using nanocapsules containing CRISPR-Cas9 ribonucleoproteins.

Genome editing of somatic cells via clustered regularly interspaced short palindromic repeats (CRISPR) offers promise for new therapeutics to treat a variety of genetic disorders, including neurological diseases. However, the dense and complex parenchyma of the brain and the post-mitotic state of neurons make efficient genome editing challenging. In vivo delivery systems for CRISPR-Cas proteins and single guide RNA (sgRNA) include both viral vectors and non-viral strategies, each presenting different advantages and disadvantages for clinical application.

Overcoming the Blood-Brain Barrier for Gene Therapy via Systemic Administration of GSH-Responsive Silica Nanocapsules.

CRISPR genome editing can potentially treat the root causes of many genetic diseases, including central nervous system (CNS) disorders. However, the promise of brain-targeted therapeutic genome editing relies on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which represents a major challenge in the development of CRISPR therapeutics. We created and screened a library of glutathione (GSH)-responsive silica nanocapsules (SNCs) for brain targeted delivery of biologics via systemic administration.

Multifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade.

Radiation therapy (RT) activates an in situ vaccine effect when combined with immune checkpoint blockade (ICB), yet this effect may be limited because RT does not fully optimize tumor antigen presentation or fully overcome suppressive mechanisms in the tumor-immune microenvironment. To overcome this, we develop a multifunctional nanoparticle composed of polylysine, iron oxide, and CpG (PIC) to increase tumor antigen presentation, increase the ratio of M1:M2 tumor-associated macrophages, and enhance stimulation of a type I interferon response in conjunction with RT. In syngeneic immunologically "cold" murine tumor models, the combination of RT, PIC, and ICB significantly improves tumor response and overall survival resulting in cure of many mice and consistent activation of tumor-specific immune memory.

NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis.

Sepsis is a life-threatening organ dysfunction responsible for nearly 270,000 deaths annually in the United States alone. Nicotinamide adenine dinucleotide (NAD), an immunomodulator, can potentially treat sepsis; however, clinical application of NAD is hindered by its inability to be directly taken up by cells. To address this challenge, a family of nanoparticles (NPs) loaded with either NAD or the reduced form of NAD (NADH), hereafter NAD(H)-loaded NPs, were engineered to enable direct cellular transport and replenishment of NAD(H).

pH-Responsive Polymer Nanoparticles for Efficient Delivery of Cas9 Ribonucleoprotein With or Without Donor DNA.

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) may offer new therapeutics for genetic diseases through gene disruption via nonhomologous end joining (NHEJ) or gene correction via homology-directed repair (HDR). However, clinical translation of CRISPR technology is limited by the lack of safe and efficient delivery systems. Here, facilely fabricated pH-responsive polymer nanoparticles capable of safely and efficiently delivering Cas9 ribonucleoprotein alone (termed NHEJ-NP, diameter = 29.

Injectable Hydrogel Capable of In Situ Covalent Crosslinking for Permanent Embolization.

Vascular embolization provides an effective approach for the treatment of hemorrhage, aneurysms, and other vascular abnormalities. However, current embolic materials, such as metallic coils and liquid embolic agents, are limited by their inability to provide safe, consistent, and controlled embolization. Here, we report an injectable hydrogel that can remain at the injection site and subsequently undergo in situ covalent crosslinking, leading to the formation of a dual-crosslinking network (DCN) hydrogel for endovascular embolization.

Biomimetic, ROS-detonable nanoclusters - A multimodal nanoplatform for anti-restenotic therapy.

The long-term success of endovascular intervention has long been overshadowed by vessel re-occlusion, also known as restenosis. Mainstream anti-restenotic devices, such as drug-eluting stent (DES) and drug-coated balloon (DCB), were recently shown with suboptimal performances and life-threatening complications, thereby underpinning the urgent need for alternative strategies with enhanced efficacy and safety profile. In our current study, we engineered a multimodal nanocluster formed by self-assembly of unimolecular nanoparticles and surface coated with platelet membrane, specifically tailored for precision drug delivery in endovascular applications.

External stimuli-responsive nanoparticles for spatially and temporally controlled delivery of CRISPR-Cas genome editors.

The CRISPR-Cas9 system is a powerful tool for genome editing, which can potentially lead to new therapies for genetic diseases. To date, various viral and non-viral delivery systems have been developed for the delivery of CRISPR-Cas9 . However, spatially and temporally controlled genome editing is needed to enhance the specificity in organs/tissues and minimize the off-target effects of editing.

In vivo targeted delivery of nucleic acids and CRISPR genome editors enabled by GSH-responsive silica nanoparticles.

The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells.

An adventitial painting modality of local drug delivery to abate intimal hyperplasia.

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation.

Ultrathin micromolded 3D scaffolds for high-density photoreceptor layer reconstruction.

Polymeric scaffolds are revolutionizing therapeutics for blinding disorders affecting the outer retina, a region anatomically and functionally defined by light-sensitive photoreceptors. Recent engineering advances have produced planar scaffolds optimized for retinal pigment epithelium monolayer delivery, which are being tested in early-stage clinical trials. We previously described a three-dimensional scaffold supporting a polarized photoreceptor monolayer, but photoreceptor somata typically occupy multiple densely packed strata to maximize light detection.

Hydrogen peroxide-responsive platelet membrane-coated nanoparticles for thrombus therapy.

Occlusion of blood vessels caused by thrombi is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombi can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (HO)-scavenging ability.

A Dual-Responsive Antibiotic-Loaded Nanoparticle Specifically Binds Pathogens and Overcomes Antimicrobial-Resistant Infections.

Antimicrobial resistant (AMR) infections are a growing threat to public health and there is a general lack of development in new antibiotics. Here, a dextran-coated stimuli-responsive nanoparticle (NP) that encapsulates the hydrophobic antibiotic, rifampicin, and specifically binds bacteria to overcome AMR infections is reported. The NP shows a strong affinity with a variety of pathogens in vitro and effectively accumulates in the bacterial infected tissues.

Biomimetic fibrin-targeted and HO-responsive nanocarriers for thrombus therapy.

Thrombosis is a principle cause of various life-threatening cardiovascular diseases. However, current antithrombotic treatments using drugs only offer limited efficacy due to short half-life, low targeting ability to the thrombus site, and unexpected bleeding complications. Taking into account of the biological characteristics of thrombus including upregulation of hydrogen peroxide (HO) and abundance of fibrin, we engineered a HO-responsive nanocarrier for thrombus-targeting delivery of an antithrombotic agent (i.

Crosslinked polymer nanocapsules for therapeutic, diagnostic, and theranostic applications.

Crosslinked polymer nanocapsules (CPNCs) are hollowed nanoparticles with network-like polymeric shells stabilized by primary bonds. CPNCs have drawn broad and significant interests as nanocarriers for biomedical applications in recent years. As compared with conventional polymeric nanoparticles systems without cavity and/or crosslinking architectures, CPNCs possess significant biomedical relevant advantages, including (a) superior structural stability against environmental conditions, (b) high loading capacity and ability for region-specific loading of multiple cargos, (c) tuneable cargo release rate via crosslinking density, and (d) high specific surface area to facilitate surface adsorption, modification, and interactions.

A pH-responsive silica-metal-organic framework hybrid nanoparticle for the delivery of hydrophilic drugs, nucleic acids, and CRISPR-Cas9 genome-editing machineries.

Efficient delivery of hydrophilic drugs, nucleic acids, proteins, and any combination thereof is essential for various biomedical applications. Herein, we report a straightforward, yet versatile approach to efficiently encapsulate and deliver various hydrophilic payloads using a pH-responsive silica-metal-organic framework hybrid nanoparticle (SMOF NP) consisting of both silica and zeolitic imidazole framework (ZIF). This unique SMOF NP offers a high loading content and efficiency, excellent stability, and robust intracellular delivery of a variety of payloads, including hydrophilic small molecule drugs (e.

Double-Network Nanogel as a Nonviral Vector for DNA Delivery.

A double-network nanogel, composed of a silane-cross-linked polyethylenimine (PEI) network (i.e., PEI-S) and a pH-responsive poly(2-(hexamethyleneimino) ethyl methacrylate) (PC7A) polymer, was developed for efficient DNA transfection.