Yu Liu

Ulcerative colitis (UC) is characterized by persistent colonic inflammation accompanied by the accumulation of pro-inflammatory M1-like macrophages, which sustain cytokine production and impair mucosal repair. Promoting a shift toward a pro-resolving M2-like phenotype is therefore a promising strategy, but current macrophage-modulating approaches are often limited by insufficient intracellular drug persistence and rapid phenotypic reversion after treatment withdrawal. Herein, we report a therapeutic strategy designed to achieve prolonged immunomodulation of macrophages. Specifically, we develop an orally administrable, fusion-enabled nanoparticle (OFEN) to enable improved intracellular availability of immunomodulatory agents in macrophages. By tuning the cholesterol content of milk-derived exosome membranes, OFEN exhibited gastrointestinal stability and fusion-biased cellular entry with reduced endolysosomal sequestration. Following cellular uptake, the poly(lactic-co-glycolic acid) (PLGA) core served as an intracellular reservoir for the prolonged release of tumor necrosis factor-α (TNF-α) siRNA and curcumin, thereby combining sequence-specific suppression of a central inflammatory mediator with broader immunomodulatory and antioxidative regulation. This intracellular exposure sustained M2-associated phenotypic modulation and reduced pro-inflammatory cytokine production. In a chronic colitis model, intermittent OFEN administration alleviated disease activity, preserved colonic architecture, and promoted epithelial barrier-associated recovery, producing greater therapeutic benefit than 5-aminosalicylic acid (5-ASA) and the less fusogenic counterpart under the same intermittent dosing schedule. In a dextran sulfate sodium (DSS) rechallenge model, protective effects remained detectable at the day-12 assessment following a single oral administration of OFEN. Collectively, these findings support fusion-biased, depot-like intracellular retention as a strategy for prolonging macrophage-directed immunomodulation in UC.

Liver fibrosis lacks effective therapies largely due to the inability of conventional lipid nanoparticles (LNPs) to target activated hepatic stellate cells (HSCs), the primary drivers of fibrotic progression. Here, we developed a fibroblast activation protein inhibitor (FAPi)‐modified LNP encapsulating heat shock protein 47 (HSP47) siRNA (FAPi‐LNP/siHSP47) to target activated HSCs. FAPi‐LNP/siHSP47 exhibited enhanced HSC targeting, efficient HSP47 silencing, reduced alpha‐smooth muscle actin (α‐SMA) expression, and marked attenuation of collagen deposition in vivo. Pharmacokinetic and protein corona analyses revealed that DSPE‐PEG‐based LNPs displayed prolonged circulation and increased area under the curve (AUC) compared with DMG‐PEG formulations, while FAPi modification further enhanced AUC and reduced adsorption of complement protein C3 and apolipoprotein E (ApoE), thereby decreasing hepatocyte uptake. Importantly, acute toxicity evaluation demonstrated favorable in vivo biocompatibility without hematological, inflammatory, or histopathological abnormalities. Collectively, FAPi modification enabled LNPs to specifically target activated HSCs, providing a safe and effective treatment for liver fibrosis and presenting a new strategy for directing LNPs to cells beyond hepatocytes.

Objective: Conventional progesterone (P4) formulations suffer from low bioavailability, severe local irritation, and poor patient adherence due to P4’s poor aqueous solubility. This work aimed to develop and screen a biodegradable PLGA/NMP (Poly(lactic-co-glycolic acid)/N-methyl-2-pyrrolidone) injectable in situ gel for sustained P4 delivery to overcome these clinical limitations. Significance: Commercial oral, vaginal, and oil-based intramuscular P4 preparations cannot maintain stable long-term drug exposure, and they cause injection-site pain/inflammation. The screened in situ depot system reduces administration frequency and local tissue irritation, supporting convenient luteal phase support and pregnancy maintenance. Methods: Nine formulations with variable P4 loading (10–50% w/w) and PLGA concentration (15–55% w/w) were fabricated. Formulations were screened via three core endpoints: injectability (injection force and discharge rate), in vitro sustained release in 10% Hydroxypropyl-β-cyclodextrin (HP-β-CD)-Phosphate-buffered saline (PBS) sink medium, and 7-day subcutaneous histocompatibility in rats. high-performance liquid chromatography (HPLC) was validated for progesterone quantification; Hematoxylin and eosin (H&E) staining assessed local inflammatory responses. Results: Formulations with progesterone ≤ 30% w/w and PLGA ≤ 35% w/w exhibited acceptable injectability (injection force < 50 N; discharge rate > 79%). Higher PLGA concentrations suppressed initial burst release (16.74% at 8 h for 35% PLGA vs. 29.8% for 20% PLGA). All formulations formed stable ellipsoidal subcutaneous depots and completed progesterone release within 4 days. Histopathology revealed only mild local inflammation (histological score = 1) without severe necrosis, superior to highly irritating oil injections in formulation control groups. Conclusions: The screened PLGA-based progesterone in situ gel resolves critical drawbacks of traditional progesterone dosage forms. This low-irritation, sustained-release injectable platform provides a scalable industrial formulation candidate for long-acting hormone therapy.

Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.

Gene therapy brings a ray of hope for inherited ocular diseases that may cause severe vision loss and even blindness. However, due to the dynamic and static absorption barriers, it is challenging to deliver genes to the posterior segment of the eye by topical instillation. To circumvent this limitation, we developed a penetratin derivative (89WP)-modified polyamidoamine polyplex to deliver small interference RNA (siRNA) via eye drops to achieve effective gene silencing in orthotopic retinoblastoma. The polyplex could be spontaneously assembled through electrostatic and hydrophobic interactions, as demonstrated by isothermal titration calorimetry, and enter cells intactly. In vitro cellular internalization revealed that the polyplex possessed higher permeability and safety than the lipoplex composed of commercial cationic liposomes. After the polyplex was instilled in the conjunctival sac of the mice, the distribution of siRNA in the fundus oculi was significantly increased, and the bioluminescence from orthotopic retinoblastoma was effectively inhibited. In this work, an evolved cell-penetrating peptide was employed to modify the siRNA vector in a simple and effective way, and the formed polyplex interfered with intraocular protein expression successfully via noninvasive administration, which showed a promising prospect for gene therapy for inherited ocular diseases.

To investigate the potential of sorafenib (SF) in preoperative chemotherapy for cervical cancer to reduce tumor volume, sorafenib micelles (SF micelles) with good stability and high drug loading were designed. SF micelles were prepared by film hydration followed by the ultrasonic method. The results showed that the SF micelles were spherical with an average particle size of 67.18 ± 0.66 nm (PDI 0.17 ± 0.01), a considerable drug loading of 15.9 ± 0.46% (w/w%) and satisfactory stability in buffers containing plasma or not for at least 2 days. In vitro release showed that SF was gradually released from SF micelles and almost completely released on the third day. The results of in vitro cellular intake, cytotoxicity and proliferation of cervical cancer cell TC-1 showed that SF micelles were superior to sorafenib (Free SF). For intravaginal administration, SF micelles were dispersed in HPMC (SF micelles/HPMC), showed good viscosity sustained-release profiles in vitro and exhibited extended residence in intravaginal in vivo. Compared with SF micelles dispersed in N.S. (SF micelles/N.S.), SF micelles/HPMC significantly reduced tumor size with a tumor weight inhibition rate of 73%. The results suggested that SF micelles had good potential for preoperative tumor shrinkage and improving the quality life of patients.