Biofilm-associated infection and persistent inflammation make osteomyelitis difficult to eradicate while preserving the capacity for bone repair. Here, we developed an injectable gelatin hydrogel crosslinked by microbial transglutaminase and containing polarized barium titanate (BTO) nanoparticles (mTG-Gel/BTO). The material exhibited pressure-responsive electrical output. Pulsed ultrasound (US) exposure at device settings of 1.5 W cm⁻², 1 MHz, and 50
Rare-earth-based near-infrared (NIR) fluorescence probes with narrow multi-peak emission, long luminescence lifetimes, and high photostability are highly desirable for bioimaging. Nevertheless, such probes remain largely underdeveloped due to poor biodegradability, sophisticated synthetic procedures, and complicated photophysical modulation. Herein, neodymium (Nd) was screened from the entire series of lanthanide-containing rare-earth elements, and we developed Nd-tetrakis(4-carboxyphenyl) porphyrin (TCPP) metal-organic framework (MOF) nanoprobes. Interestingly, within this MOF assembly, the Nd-TCPP coordination creates a highly ordered rigid architecture, suppressing non-radiative transitions and dramatically boosting NIR-II emission peaking at 1060 nm. Benefiting from spatial confinement and close donor-acceptor proximity, the proposed resonant 4f-to-triplet energy transfer (f-TET) from excited Nd3+ to TCPP is suggested to be efficiently triggered under 808 nm laser irradiation, activating photodynamic processes to generate singlet oxygen (1O2). The synthesized NTM was subsequently loaded with L-buthionine sulfoximine (BSO) followed by PEGylation to obtain NTMBP nanoprobes. Upon systemic administration, the nanoprobes efficiently accumulated at tumor sites and produced durable, bright NIR-II fluorescence under 808 nm laser excitation, enabling clear visualization of tumor boundaries for precise phototherapy guidance. Meanwhile, under irradiation with the same wavelength, the NTMBP nanoprobes could generate 1O2 for tumor photodynamic therapy (PDT). In addition, BSO could deplete intracellular glutathione (GSH) to weaken antioxidant defenses, amplifying oxidative stress, and inducing robust tumor cell death. Our nanoprobe with favorable biocompatibility and biodegradability exhibited outstanding capabilities for NIR-II fluorescence imaging-guided PDT, holding great promise for further precise cancer theranostics.
The progression of intervertebral disc degeneration (IDD) is accompanied by mitochondrial dysfunction and ferroptosis in nucleus pulposus cells (NPCs), highlighting the need for further investigation into mitochondrial homeostasis-related mechanisms and targeted therapeutic strategies. We found that the mitochondrial protein GSTK1 is downregulated in degenerative NPCs, whereas its overexpression partially delays IDD progression in rats. Mechanistically, the GSTK1-ALDH1L2 axis exerts anti-ferroptotic effects by maintaining mitochondrial homeostasis, independently of the classical ACSL4 pathway. GSTK1 also promotes the formation of mitochondria-containing extracellular vesicles through CD38/IP3R/Ca2+-associated signaling. Based on these findings, we generated mitochondria-enriched extracellular vesicles derived from GSTK1-overexpressing NPCs (Super-Mito-EV), modified them with EY3 to enhance targeted mitochondrial transfer, and incorporated them into a thermosensitive hydrogel to construct an injectable sustained-release delivery system. In a rat IDD model, this strategy significantly delayed IDD and improved disc structure and molecular homeostasis. In summary, our findings reveal the role of GSTK1–ALDH1L2-mediated mitochondrial homeostasis in IDD-associated ferroptosis and propose a targeted therapeutic strategy based on Super-Mito-EV-mediated mitochondrial delivery.
Immune checkpoint blockade has improved cancer treatment outcomes, yet many solid tumors remain immunologically “cold” and resistant to therapy. Tertiary lymphoid structures (TLSs) are linked to enhanced survival and response rates, but germinal center-like TLSs are challenging to generate in subcutaneous tumors due to rapid clearance of soluble inductive signals. We engineered an injectable supramolecular hydrogel to co-deliver liposome-formulated mRNAs encoding CXCL13 and LIGHT, thereby stabilizing the complexes and extending intratumoral cytokine production. In murine B16.f10, CT26, and 4T1 subcutaneous tumor models, this strategy increased TLS density and maturation, suppressed tumor growth, and prolonged survival. Combination with PD-1 blockade yielded enhanced efficacy antitumor effects, achieving complete tumor regression in some cases. Our results support the development of a novel injectable hydrogel-encapsulated formulation in combination with liposomes for enhancing the efficacy of mRNA therapeutics against cancer.
Musculoskeletal repair is jointly constrained by impaired inflammation resolution, elevated oxidative stress, diminished regenerative capacity, and altered mechanical microenvironments. Here, we develop a cell-free reparative strategy based on exosomes derived from YAP-activated M2-like macrophages, integrated with reactive oxygen species (ROS)-responsive hydrogel delivery. Pharmacological activation of YAP under low-stiffness conditions partially recapitulates the reparative macrophage phenotype induced by matrix stiffening. Exosomes harvested from YAP-activated macrophages (Y-M2-EXO) exhibit stronger anti-inflammatory, antioxidant, and pro-regenerative activities than conventional M2 macrophage-derived exosomes (M2-EXO), mitigating oxidative injury and lipid peroxidation-associated cellular damage in mesenchymal stem cells (MSCs), preserving mitochondrial homeostasis, and enhancing MSC migration, proliferation, and osteogenic/tenogenic differentiation. MicroRNA sequencing and qRT-PCR validation reveal that YAP activation markedly reshapes the miRNA profile of Y-M2-EXO, enriching a candidate miRNA network associated with inflammatory stress, differentiation and regeneration, senescence homeostasis, and mechano-adaptation, which provides a molecular explanatory framework for the functional superiority of Y-M2-EXO over M2-EXO. To improve local retention and environmentally triggered release, Y-M2-EXO are encapsulated within an ROS-responsive hydrogel dynamically crosslinked by hyaluronic acid-aminophenylboronic acid (HA-APBA) and poly(vinyl alcohol) (PVA). In rat models of Achilles tendon rupture and tibial fracture, hydrogel-delivered Y-M2-EXO ameliorate the injured microenvironment, promote structural tissue reconstruction and biomechanical recovery, and maintain robust reparative performance under conditions of restricted mechanical input. In naturally aged mice, Y-M2-EXO reduce the senescence-associated secretory phenotype (SASP)-related inflammatory burden and alleviate bone and muscle degeneration; when combined with aerobic exercise, selected tissue reconstruction and motor function parameters are further improved. Collectively, this study supports donor-cell YAP preprogramming to optimize exosome bioactivity, coupled with ROS-responsive local delivery, as a translationally promising cell-free regulatory strategy for musculoskeletal repair.
