Ugi-reaction-derived ionizable lipids with cyclic tertiary amine heads enable spleen-targeted mRNA delivery.

Lipid nanoparticles (LNPs) have become an important platform for nucleic acid delivery. However, LNP-mediated delivery to non-hepatic organs and specific cell types remains a non-negligible challenge. As a key component of LNPs, ionizable lipids were rationally designed to adjust the LNPs properties to achieve organ-targeted delivery.

Pathology-inspired collagen-binding thermosensitive micelle drops enable prolonged and efficient treatment of fungal keratitis.

Fungal keratitis (FK) is a challenging-to-manage blinding corneal infectious disease that often leads to severe sequelae, such as corneal leukoplakia regardless of curative care. Moreover, the unique anatomical structure and tear turnover of the eye significantly limit the bioavailability and therapeutic efficacy of traditional eye drops. Inspired by the unique pathological features of corneal ulcers, we report a thermosensitive multifunctional eye drop, designated PX-TA, based on a poloxamer (PX) and a collagen-adhesive tannic acid (TA), for prolonged and efficient treatment of FK.

Responsive Microneedles for Diagnostic and Therapeutic Applications of Ocular Diseases.

Traditional ophthalmic formulations are characterized by low bioavailability, short intraocular retention time, strong irritation, and failure to achieve the expected therapeutic effect due to the special physiological structure of the eye and the existence of many barriers. Microneedle drug delivery is a novel transdermal drug delivery modality. Responsive microneedles are defined as controllably releasing the drug payloads in response to physiological stimuli, including pH levels, temperature, enzymes, and reactive oxygen species (ROS), as well as external stimuli such as magnetic fields and light.

Protein Corona of Nanoparticles: Isolation and Analysis.

Nanoparticles entering biological systems or fluids inevitably adsorb biomolecules, such as protein, on their surfaces, forming a protein corona. Ensuing, the protein corona endows nanoparticles with a new biological identity and impacts the interaction between the nanoparticles and biological systems. Hence, the development of reliable techniques for protein corona isolation and analysis is key for understanding the biological behaviors of nanoparticles.

ROS-Responsive Microneedle Patches Enable Peri-Lacrimal Gland Therapeutic Administration for Long-Acting Therapy of Sjögren's Syndrome-Related Dry Eye.

Sjögren's syndrome-related dry eye (SSDE) is a severe dry eye subtype characterized by significant immune cell attacks on the lacrimal gland. However, delivering immunosuppressive drugs to the lacrimal glands for SSDE therapy safely and sustainably poses significant challenges in clinical practice. Herein, a ROS-responsive microneedle patch with detachable functionality (CE-MN) is developed to enable straightforward and minimally invasive administration to the lacrimal gland area by penetrating the periocular skin.

Enhanced bone regeneration by osteoinductive and angiogenic zein/whitlockite composite scaffolds loaded with levofloxacin.

Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method.

Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy.

Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR)-poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously co-administered the nanomedicine with the tumor-penetrating peptide iRGD for enhanced treatment of pancreatic tumor.

Type I Collagen-Adhesive and ROS-Scavenging Nanoreactors Enhanced Retinal Ganglion Cell Survival in an Experimental Optic Nerve Crush Model.

Traumatic optic neuropathy (TON) is a severe condition characterized by retinal ganglion cell (RGC) death, often leading to irreversible vision loss, and the death of RGCs is closely associated with oxidative stress. Unfortunately, effective treatment options for TON are lacking. To address this, catalase (CAT) is encapsulated in a tannic acid (TA)/poly(ethylenimine)-crosslinked hollow nanoreactor (CAT@PTP), which exhibited enhanced anchoring in the retina due to TA-collagen adhesion.

Drug content on anticancer efficacy of self-assembling ketal-linked dextran-paclitaxel conjugates.

Although polymer-drug conjugates (PDCs) show great promise as versatile drug delivery systems, no antitumor PDCs based on small-molecule drugs are currently on the market, partly because of the lack of validated design principles for PDCs. High drug content is thought to be essential for devising highly efficacious PDCs based on poorly soluble antitumor drugs, but this has not been well validated. Therefore, revisiting the relationship between drug content and PDC performance is vital.

Fine-tuning the sequential drug release of nano-formulated mutual prodrugs dictates the combination effects.

The maintenance of robust ratiometric loading of dual therapeutic agents and fine-tuning release kinetics for consistent and optimization of combination effects is vital for discovering new anticancer drug combinations and remains challenging. Smart nanomedicine strategies have been investigated for this purpose, but most of the reported strategies focus either on ratiometric delivery or on unimodal sequential release of the two different agents, which hampers effective optimization of combination effects. Herein we report a sequential drug release system based on nanoformulated mutual prodrugs constructed by the formation of ketal linkages with different acid sensitivities, thus enabling the acid-triggered release of two anticancer drugs, paclitaxel and gemcitabine, in various sequences.

Long-acting acid-sensitive ketal-linked dexamethasone microcrystals for treating experimental autoimmune uveitis.

Corticosteroids have for some time been used as first-line drugs for the topical treatment of noninfectious uveitis, but poor ocular bioavailability and the rapid clearance of eye drops necessitate frequent dosing, reducing patient compliance. In this study, we used an acid-sensitive stearoxyl-ketal-dexamethasone pro-drug microcrystals (SKD MCs), which is consistently safe and effective in the control of uveitis inflammation in rats. We used a rat model of experimental autoimmune uveitis (EAU) to evaluate the effects of SKD MCs in terms of clinical manifestations, molecular biology, pathological histology, and visual electrophysiology compared to dexamethasone sodium phosphate injection or phosphate-buffered saline.

Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy.

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy.

The Yin and Yang of the protein corona on the delivery journey of nanoparticles.

Nanoparticles-based drug delivery systems have attracted significant attention in biomedical fields because they can deliver loaded cargoes to the target site in a controlled manner. However, tremendous challenges must still be overcome to reach the expected targeting and therapeutic efficacy . These challenges mainly arise because the interaction between nanoparticles and biological systems is complex and dynamic and is influenced by the physicochemical properties of the nanoparticles and the heterogeneity of biological systems.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics.

Carrier strategies boost the application of CRISPR/Cas system in gene therapy.

Emerging clustered regularly interspaced short palindromic repeat/associated protein (CRISPR/Cas) genome editing technology shows great potential in gene therapy. However, proteins and nucleic acids suffer from enzymatic degradation in the physiological environment and low permeability into cells. Exploiting carriers to protect the CRISPR system from degradation, enhance its targeting of specific tissues and cells, and reduce its immunogenicity is essential to stimulate its clinical applications.

Spatiotemporal Tracing of the Cellular Internalization Process of Rod-Shaped Nanostructures.

Endocytosis, as one of the main ways for nanostructures enter cells, is affected by several aspects, and shape is an especially critical aspect during the endocytosis of nanostructures. However, it has remained challenging to capture the dynamic internalization behaviors of rod-shaped nanostructures while also probing the mechanical aspects of the internalization. Here, using the atomic force microscopy-based force tracing technique, transmission electron microscopy, and molecular dynamic simulation, we mapped the detailed internalization behaviors of rod-shaped nanostructures with different aspect ratios at the single-particle level.

Self-Assembly of Podophyllotoxin-Loaded Lipid Bilayer Nanoparticles for Highly Effective Chemotherapy and Immunotherapy via Downregulation of Programmed Cell Death Ligand 1 Production.

Low drug delivery efficiency elevates the cost of medication, lowers the therapeutic efficacy, and appears as a leading reason for unmet needs in anticancer therapies. Herein, we report the development of self-assembled podophyllotoxin-loaded lipid bilayer nanoparticles that inhibit the production of programmed cell death ligand 1 in lung cancer cells and promote tumor-specific immune responses, thus offering a strategy for regulating the immunosuppressive microenvironment of tumors. In addition, encapsulation of podophyllotoxin in the nanoparticles reduced its systemic toxicity, enhanced its penetration into tumors, and increased its antitumor efficacy.

Graphene Oxide/Chitosan/Hydroxyapatite Composite Membranes Enhance Osteoblast Adhesion and Guided Bone Regeneration.

Two-dimensional materials provide a secluded space for bone formation and preserve the growth of surrounding tissues, thus playing a crucial role in guided bone regeneration (GBR). Graphene oxide (GO) has been widely employed in GBR due to its good mechanical and hydrophilic properties. A single GO membrane, however, does not provide a friendly environment for osteogenic cell adhesion.

Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols.

Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis.

Intra-Articular injection of acid-sensitive stearoxyl-ketal-dexamethasone microcrystals for long-acting arthritis therapy.

Despite advances in treatment of chronic arthritis, there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues. In this work, we fabricated microcrystals of an acid-sensitive stearoxyl-ketal-dexamethasone prodrug for treatment of arthritis. Microcrystals of the prodrug with two sizes were successfully engineered and showed pH-dependent hydrolysis kinetics .