Yu Zhang

A half-sandwich iridium(III) complex, [(η⁵-Cp*)Ir(Py-BIAN)Cl]PF₆, bearing a pyrene-substituted α-diimine ligand (Py-BIAN), has been synthesized and fully characterized. Single-crystal X-ray diffraction reveals a three-legged piano-stool geometry with κ²N,N′-chelating Py-BIAN and a terminal chloride. DFT benchmarking at six levels identifies CAM-B3LYP/def2-SVP/def2-TZVP as the best-performing method, which was then used to investigate the frontier molecular orbitals, ESP, UV-vis and FT-IR spectra, and excited-state energy levels. To understand how the pyrene-extended aromatic surface controls the solid-state organization, the intermolecular interactions were analyzed by a combination of IGMH, energy decomposition, and Hirshfeld surface methods. IGMH and Hirshfeld surface analyses reveal four C–H···X (X = Cl, F) hydrogen bonds and three π–π stacking interactions, with an interaction energy of −10.34 kcal mol⁻¹ between the two closest cationic complexes. Energy decomposition analysis shows that Complex···PF₆⁻ ion pairs are dominated by the Coulombic term (−303.50 to −181.56 kJ mol⁻¹), whereas Complex···Complex pairs are net repulsive (+26.51 to +48.25 kJ mol⁻¹) with a significant dispersion contribution (up to −107.78 kJ mol⁻¹). This work provides the first example of a pyrene-substituted BIAN–iridium(III) complex and a combined experimental and theoretical basis for understanding how the pyrene-extended BIAN environment controls its structure, electronic structure, and packing.

Vitreous floaters affect >80% of people over 60, severely impairing quality of life, yet no safe and effective treatment exists. Nd/YAG laser vitreolysis requires dangerously high fluences, risking retinal injury, and fails to address the underlying pathological cascade. Here, we report a laser-triggered cluster nanobomb (PDN-C) for ultralow-fluence vitreolysis and homeostasis restoration. The nanobomb comprises a magnetic iron-oxide core and targeting-peptide-linked bullets. It actively penetrates the viscous vitreous and anchors to pathological collagen aggregates. Upon pulsed-laser irradiation at a fluence ∼1000-fold lower than clinical Nd/YAG therapy, the core converts the laser into localized microbubble cavitation that ejects the bullets and ablates >87% of collagen mass without retinal phototoxicity. Mechanistically, the ejected bullets achieve a dual-biochemical blockade of the pathogenic ROS-MMP axis: doxycycline inhibits MMP-driven type IV collagen degradation, while the ultrananozyme scavenges ROS, delaying vitreous liquefaction. By coupling precision photomechanical ablation with dynamic microenvironment remodeling, this nanobomb offers a highly effective and safe translational paradigm for vitreous floaters, addressing both the symptoms and the underlying disease pathology.

This study developed a liquid self-emulsifying drug delivery system (BIBF-SEDDS, size 23.83 nm, zeta 20.5 mV) to enhance nintedanib (BIBF) oral bioavailability. BIBF-SEDDS was encapsulated in pH-sensitive calcium alginate gel microspheres (BIBF-S-SEDDS). Eudragit L100 (precipitation inhibitor) and PEG 400 (porogenic agent) were further added to obtain porous BIBF-S-SEDDS. In vitro dissolution and in vivo pharmacokinetics in rats were compared with imitation soft capsules. Porous BIBF-S-SEDDS increased oral bioavailability by 2.11-fold, prolonged Tmax, reduced gastric irritation (HE staining), and improved intestinal absorption. Liver enzyme (ALT/AST) levels suggested better safety. A chylomicron blockade model indicated lymphatic transport as an auxiliary absorption pathway. Accelerated stability (6 months, 40°C/75% RH) showed no significant changes in appearance, drug content, or dissolution. This multistage delivery system offers a promising strategy for oral BIBF administration.

CDK4/6 inhibitor-induced myelosuppression frequently necessitates treatment interruption or dose reduction, yet effective pharmacological interventions specifically addressing this persistent hematological toxicity remain limited. Here, we report a porosity-programmed protopanaxadiol-loaded PLGA microsphere (PPD-MS) system for rapid-onset and long-acting myeloprotection during anticancer treatment. Using a continuous-flow O/W microsphere fabrication strategy, microsphere porosity and core–shell architecture were precisely regulated by tuning aqueous-phase osmotic pressure, establishing a controllable process–structure–release relationship. The optimized PPD-MS rapidly achieved a stable plasma plateau within 0.5 h after intramuscular injection and maintained sustained systemic exposure for 19 days, with a strong in vitro–in vivo correlation between release profiles (R² = 0.9983). Their narrow particle-size distribution enabled smooth administration through a 26G needle, supporting clinical feasibility. In chemotherapy- and CDK4/6 inhibitor-induced myelosuppression models, PPD-MS effectively restored peripheral blood cell counts, bone marrow cellularity, and hematopoietic stem and multipotent progenitor populations. Mechanistically, PPD-MS rescued hematopoietic cell-cycle progression by activating PI3K/AKT signaling, suppressing p21-mediated inhibition, and restoring the Rb/E2F1–Cyclin E/CDK2 axis, thereby reversing CDK4/6 inhibitor-induced G1/S arrest. Moreover, combination treatment with paclitaxel or CDK4/6 inhibition enhanced antitumor efficacy, accompanied by increased cytotoxic immune activation and reduced PD-L1-associated immune escape. Collectively, this study establishes a porosity-engineered long-acting microsphere platform that integrates predictable drug release, rapid and sustained myeloprotection, and improved combination anticancer therapy, providing a translational strategy for managing CDK4/6 inhibitor-associated hematological toxicity.

Cabazitaxel (CTX) exhibits potent antineoplastic activity and is demonstrated to promote antitumor immunity by triggering immunogenic cell death (ICD). This is commonly used in the clinical treatment of advanced and metastatic triple-negative breast cancer (TNBC). However, the therapeutic index of commercial CTX injections is severely restricted by their definite systemic toxicity and low tolerability. Herein, we developed biomimetic low-density lipoprotein nanoparticles (CTX2TK&VP@LDL NPs) by integrating ROS-responsive CTX dimeric prodrugs (CTX2TK) and the photosensitizer verteporfin (VP) into LDL NPs to selectively target tumors and achieve synergistic chemophotodynamic therapy and immunotherapy for TNBC with improved biosafety. CTX2TK&VP@LDL NPs were able to enhance the accumulation and cellular uptake in 4T1 tumors overexpressing LDL receptor, improving the targeted codelivery efficiency. When CTX2TK&VP@LDL NPs were deposited at the tumor sites, localized 1O2 was generated upon irradiation for triggering ultrafast CTX release with low premature CTX leakage in the off-target tissue. Additionally, the generated 1O2 can further synergistically reinforce ICD and elicit robust antitumor immune activation. The combination treatment with CTX2TK&VP@LDL NPs and PD-L1 blockade notably inhibited abscopal tumor growth and lung metastasis. Taken together, the biomimetic CTX2TK&VP@LDL NPs exploit endogenous LDL functionality to enable receptor-mediated tumor targeting and synergistic chemophotodynamic immune activation, providing an effective and safe therapeutic strategy for TNBC.

Mycoplasma pneumoniae pneumonia (MPP) is a major cause of community-acquired pneumonia in children, and azithromycin (AZM) is recommended as a first-line macrolide for its treatment. However, current oral and intravenous AZM formulations require high systemic doses to achieve effective pulmonary concentrations, thereby increasing the risk of adverse effects (e.g., gastrointestinal reactions, cardiotoxicity) and antibiotic resistance. In this study, we developed an azithromycin liposomal formulation (AC-Lip) for local pulmonary administration, enabling direct targeting of pulmonary lesions while reducing the required dose and enhancing pulmonary bioavailability. To achieve efficient drug loading, an ion-pairing strategy was employed to increase the lipophilicity of AZM through complexation with cholesteryl hemisuccinate. The resulting AC-Lip displayed a spherical morphology with an average particle size of approximately 120 nm, a high encapsulation efficiency of 89.86%, and favorable long-term stability. Pharmacokinetic analysis demonstrated that, following pulmonary administration, the absolute pulmonary bioavailability of AZM from AC-Lip was 6.52-fold higher than that of intravenous AZM injection. Preliminary nebulization stability studies further supported its feasibility as an inhalable formulation. Collectively, these findings indicate that AC-Lip enables efficient pulmonary-targeted delivery of AZM and holds substantial promise as a novel clinical therapeutic strategy for the treatment of MPP.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible interstitial lung disease with an extremely high mortality rate. The FDA-approved oral nintedanib is a standard treatment requiring frequent long-term administration, causing poor patient compliance, plasma drug concentration fluctuations, and hepatotoxicity. To overcome the drawbacks of frequent dosing and unstable drug exposure, we developed nintedanib-loaded microspheres (NDNB-MS) with biphasic release profile, achieving sustained drug release for up to 55 days. Notably, during Phase I (0-7 days), drug release was primarily driven by surface dissolution and diffusion from the microsphere surface, achieving a 24-hour release of approximately 12% with no notable burst effect, thereby enabling prompt drug delivery. In Phase II (7-55 days), PLGA matrix degradation coupled with steady-state diffusion contributed to a constant drug release rate throughout this period, characterized by the absence of a plateau phase and without the gradual decline typically observed in later stages. In an IPF animal model, the biphasic release of NDNB-MS translated into distinct therapeutic benefits: the initial rapid release without burst effect enabled prompt drug delivery during the early phase, the sustained constant release phase provided continuous inhibition of the transforming growth factor-beta (TGF-β)/Smad2/3 signaling pathway, as well as long-term suppression of fibroblast-to-myofibroblast transformation, thereby preventing excessive extracellular matrix (ECM) deposition. This formulation overcomes key clinical drawbacks of oral nintedanib, providing a new drug delivery strategy for IPF that is long-acting, stable, and highly compliant, with significant clinical translational value and application prospects.