Inflammatory and immune-mediated ocular diseases encompass a spectrum of conditions that arise from dysregulated immune-inflammatory responses marked by a chronic clinical course, a propensity for relapse, and a tendency to cause significant ocular tissue damage, which can lead to profound impairment of visual function. Dysregulation of the balance between immune cell subpopulations is central to the pathogenesis of many of these diseases. At present, non-specific treatments such as glucocorticoids and immunosuppressants form the cornerstone of therapy for inflammatory and immune-mediated ocular diseases. However, these treatments often suffer from poor bioavailability and targeting, cumbersome or invasive administration methods, and are associated with side effects such as increased intraocular pressure (IOP), cataracts, or glaucoma with frequent administration. These limitations underscore the urgent need for alternative drug delivery methods. Microneedles have emerged as an innovative approach to ocular drug delivery, offering distinct advantages over traditional eye drops and intravitreal injections. They enhance drug penetration and targeting, provide sustained release, and may reduce unnecessary drug exposure, thus holding great promise for the treatment of inflammatory and immune-mediated ocular diseases. This review aims to shed light on the unique benefits and efficacy of microneedles as drug-delivery systems for inflammatory and immune-mediated ocular diseases, with particular attention to noninfectious uveitis, corneal inflammatory disorders, inflammation-associated corneal neovascularization, and allergic conjunctivitis. It also discusses ocular safety and toxicity, manufacturing and standardization, regulatory challenges, and future prospects of microneedle applications, providing a comprehensive overview of their potential for ocular drug delivery.
Efficient delivery of plasmid DNA (pDNA) into the nucleus remains a major bottleneck in nonviral gene therapy, particularly in post-mitotic and slowly dividing cells where the nuclear envelope constitutes a permanent barrier to passive entry. This review considers the two main strategies for active nuclear targeting: nuclear localisation signal (NLS) peptides, which recruit importin-α/β receptors directly to DNA cargo, and DNA nuclear targeting sequences (DTS), which exploit NLS-bearing transcription factors to mediate piggyback nuclear import. Rather than re-cataloguing nuclear import biology, we focus on the conditions under which each strategy succeeds or fails, incorporating advances in nuclear pore complex architecture and permeability, karyopherin-FG-nucleoporin electrostatics, and cytoplasmic constraints such as barrier-to-autointegration factor (BAF)-mediated clustering of exogenous DNA. NLS classes are compared with universal (SV40 enhancer), inducible (NF-κB) and tissue-specific (SMGA, SP-C, T1α) DTS elements, and four chemical coupling strategies are evaluated across peptide-, polymer- and lipid-based nanoassemblies. To address the near-absence of NLS/DTS mechanisms in current clinical pDNA programmes, we propose the Nuclear Accessibility Index (NAI): a three-axis framework integrating cell division status, carrier-DNA accessibility and intracellular signalling context. Treating the NAI as an axis vector rather than a summed score defines permissive, conditional and excluded regions of the design space. Two matter in practice: one in which highly proliferative cells render active targeting redundant, and one in which the rate-limiting problem is carrier engineering rather than the addition of a signal. The NAI offers design principles for nuclear-targeted nanocarriers and defines the preconditions for therapeutically relevant active import.
Advanced wound dressings should combine physical protection with localized and microenvironment-responsive delivery of therapeutic agents. Lycium barbarum glycopeptide (LbGp), a naturally derived macromolecular preparation with reported immunomodulatory and tissue-protective activities; however, its topical use is limited by rapid diffusion and insufficient local retention. Here, we engineered an injectable oxidized sodium alginate/gelatin hydrogel (OSA/Gel@LbGp) for localized delivery of LbGp through dynamic Schiff-base crosslinking. OSA/Gel@LbGp showed favorable cytocompatibility, promoted HaCaT keratinocyte migration, and shifted LPS-challenged macrophages toward a repair-associated phenotype, as evidenced by reduced CD68, TNF-α, and IL-1β and increased CD206, ARG-1, and TGF-β1. In a murine 5-mm full-thickness excisional wound model, OSA/Gel@LbGp accelerated wound closure, reduced granulation-tissue gaps, enhanced re-epithelialization, and improved dermal organization and collagen deposition. RNA sequencing subsequently identified 2,097 upregulated and 980 downregulated genes, revealing an ECM-centered reparative program enriched in ECM–receptor interaction, cell–matrix adhesion, and matrix-remodeling pathways, with Mmp11 emerging as a representative remodeling-associated gene. Consistent with this transcriptional findings, treated wound tissues exhibited increased collagen I/COL1A1, MMP11, and VEGF signals,and reduced inflammation-linked MMP9. Collectively, OSA/Gel@LbGp promoted wound repair by coordinating early immune modulation with subsequent ECM reconstruction. These findings establish a delivery-centered strategy for translating natural macromolecular bioactives into advanced wound dressings that improve both healing kinetics and tissue-repair quality.
The pathological microenvironment of acute gouty arthritis (AGA) features local tissue acidification and the release of a storm of pro-inflammatory cytokines. To address this dual challenge, we engineered an acid-responsive curcumin-loaded nanoparticles microneedle system (Cur-PNPs@MN) that delivers curcumin with pH-triggered release and anti-inflammatory activity. This integrated platform combines a hyaluronic acid (HA)-based dissolving microneedle for localized transdermal delivery of acid-degradable PCADK (poly (cyclohexane-1,4-diyl acetone dimethylene ketal)) curcumin nanoparticles (Cur-PNPs), which are designed for pH-triggered curcumin release at the pathological site. Together, they deliver curcumin, a dual-function agent acting both as an anti-inflammatory compound and a nanoenhanced sonosensitizer. In vitro, the system exhibited acid-responsive drug release and also promoted macrophage uptake, achieving significant curcumin accumulation within 1 hour and saturation by 4 hours. Moreover, it could generate potent ultrasound-induced reactive oxygen species (ROS). The ROS generation capability of Cur-PNPs was 1.47-fold higher than that of Cur‑aggregates, resulting in anapoptosis rate of 29.9% in M1 macrophages. In vivo, the chemo-sonodynamic therapy (Cur-PNPs@MN+Ultrasound (US)) in a rat AGA model significantly alleviated joint swelling and inflammatory infiltration, while drastically suppressing pro-inflammatory cytokines, with IL-1β decreasing from 170.3 to 67.3 pg/mL, TNF-α from 20.8 to 5.9 pg/mL, and IL-6 from 140.9 to 48.2 pg/mL, and achieved therapeutic efficacy comparable to conventional drugs. This work demonstrates a synergistic chemo‑sonodynamic strategy by coupling pH-triggered curcumin release with ultrasound-enhanced ROS generation. This acid-responsive therapeutic strategy enhances anti-inflammatory efficacy and reduction of M1-associated inflammatory responses, offering an effective approach for AGA therapy.
Efficient transport to the nuclear envelope is a prerequisite for many nucleus-targeted drug delivery strategies. We develop an enhanced, energy-based simulation of spherical nanoparticle (NP) complexes hauled by multiple dynein motors via flexible polymer linkers, aimed at deriving design rules for nucleus-directed delivery. The model extends prior work by treating dynein as a semi-flexible polymer and enforcing path-wise steric exclusion along full stepping trajectories. Event propensities follow a Monte-Carlo scheme with energies that couple linker entropy, dynein bending, and binding enthalpy; post-event mechanical relaxation uses gradient descent. We compare our model results to recent motility assays of spherical NPs decorated with polyethylene-glycol (PEG) polymers, each ending with a nuclear-localisation-signal (NLS) peptide that can recruit dynein from the cytoplasm. With standardised biophysical parameters, the model captures the observed dependence on motor number: longitudinal velocity decreases with dynein load, whereas run-distance and run-time increase. For mean NP-bound motors between 1 and 6, the model results lie within the experimental 95% confidence intervals. A systematic scan of polymer contour length, for a 20 nm radius cargo hauled by six motors, reveals a clear optimum of the run-time and run-length at about 40 nm length, despite a reduction in velocity. Similar results, for different cargo sizes and motor loading, can be obtained using our model-based computer code. They can provide a quantitative basis for tuning linker contour length (and, secondarily, motor loading by tuning PEG-NLS density) when engineering NP vehicles that exploit native microtubule transport for nucleus-directed delivery.
