Soft tissue integration around implants is severely compromised by the inflammatory microenvironment, often leading to implant failure. However, due to the bioinert nature of titanium (Ti), effective strategies to regulate this microenvironment remain limited. Herein, we propose a poly(lipoic acid)-based antibacterial polymer (pLAP) enabling controlled molecular hydrogen (H2) release to achieve both antibacterial and pro-regenerative effects for this critical challenge. The pLAP exhibits potent antibacterial activity, achieving killing efficiencies of 90.71% and 94.62% against Staphylococcus aureus and Porphyromonas gingivalis, respectively. Notably, the strong adhesion of pLAP to substrate and its affinity for bacterial membranes contribute to its durable and sustained antibacterial performance. Owing to the encapsulation of H2-loaded TiO2 nanotubes within pLAP and its intrinsic biodegradability, a delayed and sustained H2 release profile is achieved, with H2 levels rising to 427 ppb within 24 h and persisting above 300 ppb for at least 72 h. In vitro and in vivo studies demonstrate that released H2 alleviates oxidative stress and modulates immune responses, with suppression of the JAK1-STAT1 and activation of the JAK3-STAT6 signaling pathways associated with these effects, promoting M2 polarization and enhancing soft tissue integration. Collectively, this work presents a robust and generalizable strategy for regulating the inflammatory microenvironment in peri-implantitis and other implant-associated inflammatory conditions.
Spinal cord injury (SCI) is a severe neurological disease resulting in the formation of a harsh microenvironment that hinders neural regeneration. By preserving the components and structure of natural tissues, the decellularized extracellular matrix (dECM) mimics the neural regeneration microenvironment and provides the biochemical signals and structural support for neural regeneration. However, the regenerated neurons lack the ability to autonomously restore neural communication. In this study, we assemble the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) within spinal cord-derived decellularized extracellular matrix (pdECM) to construct a novel pdECM-based conductive hydrogel for enhancing neural communication among regenerated neurons via biochemical and bioelectrical signaling. This conductive hydrogel induces the differentiation of neural stem cells into neurons, modulates cellular membrane potential, enhances 4-fold cellular calcium activity in neural cells, upregulates expression of calcium-dependent signaling genes, and stimulates BDNF expression. In SCI mice model, the conductive hydrogel promotes endogenous neural regeneration, and sustained activates the secretion of neurotrophic factors and calcium-dependent signaling pathways for enhancing neural communication, thereby accelerating motor function recovery. This study addresses the challenge of neural communication among regenerated neurons by activating calcium-dependent signals, providing a novel strategy for the treatment of SCI through integrated biochemical and bioelectrical signaling.
Effective T-cell activation plays the critical role in cancer immunotherapy; however, strategies to precisely and sustainably stimulate antitumor T-cell responses while minimizing systemic toxicity remain limited. Here, we develop a sonogenetic artificial antigen-presenting cell (aAPC) platform for remote, spatiotemporally controlled Ca2+ influx in tumor-infiltrating T cells. The platform consists of poly (lactic-co-glycolic acid) nanoparticles loaded with the plasmid encoding the Mechanosensitive channel of large conductance (MSCL), coated with tumor-pulsed dendritic cell membranes to provide costimulatory signals, and conjugated with PD-1-targeting aptamers for T-cell-specific delivery. The nanoplatform exhibited high gene transfection efficiency within T cells and realize the expression of US (US)-responsive MSCL on the surface of T cells. Upon US irradiation, the engineered MSCL open, triggering controlled Ca2+ influx and activating downstream NFAT signalling. Therefore, sonogenetic aAPC results in the efficient and specific synergistic activation of T cells, improves the killing effects of T cells and ameliorated the dysfunction of exhausted T cells. In B16-F10 melanoma-bearing mice, sonogenetic aAPC promotes tumor infiltration and proliferation of CD8+ T cells, reduces immunosuppressive cells, and significantly suppresses tumor growth without eliciting adverse systemic immune-related events. This work demonstrates a safe and effective strategy for remotely potentiating T-cell-mediated antitumor immunity through precise sonogenetic control of calcium signalling.
Macrophages serve as central units in immune regulation, with their polarization influencing distinct stages of the bone healing process. Here, we report an immune-adaptive 3D-printed scaffold that integrates engineered macrophage capture traps, an HA network-mediated macrophage anchoring interface, onto a poly(lactic-co-glycolic acid)/hydroxyapatite microsphere composite framework. These traps selectively enrich macrophages via CD44 receptor-mediated recognition and dynamically guide their polarization. Intramuscular implantation experiments demonstrated a sequential shift in polarization of scaffold-enriched macrophages from M1 at 3 days to M2 at 7 days. Omics analysis of the short-term rabbit calvarial defect model revealed that HA released from this scaffold is phagocytosed by macrophages, gradually enters lysosomes, and activates antioxidant pathways, including negative regulator of reactive oxygen species (NRROS), sestrin 2 (SESN2), and glucose-6-phosphate dehydrogenase (G6PD), thereby reducing intracellular levels of reactive oxygen and nitrogen species. These processes collectively drive the shift in macrophage polarization from M1 to M2, and accelerate angiogenesis and bone matrix deposition. These findings provide new insights for the design of immunomodulatory bone regenerative materials.
As the most prevalent subtype of colorectal cancer, microsatellite-stable colorectal cancer (MSS CRC) is resistant to T cell-focused immune checkpoint blockade due to its low mutational burden and immunosuppressive tumor microenvironment. Despite reprogramming tumor-associated macrophages toward a tumoricidal M1-like state being a promising alternative, its efficacy is limited by paradoxical upregulation of programmed cell death-ligand 1 (PD-L1) on M1-like macrophages and their inherently poor antigen cross-presentation capacity. Here, we report that poly-metformin (PMet) can mimic the intracellular domain of PD-L1, competitively inhibit the membrane anchoring of PD-L1, and thereby effectively downregulate cell-surface PD-L1. To evaluate the therapeutic efficacy of PMet in immunosuppressive MSS CRC, we further developed an oral probiotic outer membrane vesicle (OMV) gene delivery system, siYthdf2/PMet@Akk-OMV, and demonstrated its ability to reduce PD-L1 levels on both macrophages and tumor cells while synergistically enhancing macrophage cross-presentation of tumor antigens, leading to potent activation of specific antitumor immunity and significant tumor growth inhibition. This work thus provides both theoretical and experimental foundations for treating cancers resistant to traditional immune checkpoint blockade therapy.
