A TLR4-Targeting Bioactive Peptide Hydrogel to Regulate Immune-Microenvironment for Diabetic Wound Repair.

Persistent inflammation and disrupted immunoregulation are critical factors in impeding diabetic wound healing. While immunoregulatory hydrogel dressings hold significant promise for clinical applications in diabetic wound healing, the current application often demands intricate interventions and high-cost treatments involving cytokines and cell therapies. The development of single component immunoregulatory hydrogels remains a complex challenge. To address this issue, an active peptide hydrogel with immunoregulatory properties targeting the TLR4/NF-kB pathway, aiming to promote rapid diabetic wound healing, is engineered. The hydrogel sequence comprises naphthalene derivative, phenylalanine, and glycine to modulate hydrophilic/hydrophobic characteristics. The amino group on arginine contributes to tissue adhesion and regulation of intermolecular forces, ultimately yielding stable gels. The results underscore the formation of the peptide hydrogel (NFA) via the physical crosslinking of self-assembled nanofibers in water, thereby affording both excellent injectability and tissue adhesion. Notably, NFA demonstrates significant potential in promoting wound healing in a mouse model with full-thickness wounds by regulating macrophage responses in the inflammatory microenvironment through the TLR4/NF-kB pathway.

Adipose Tissue Targeting Ultra-Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment.

Photodynamic therapy (PDT), as a means of locally and rapidly inducing adipocyte death via light illumination, in combination with adipose browning induction, a more gradual and widespread effect that could transform white adipose tissue into thermogenic adipose tissue, manifests a promising approach to combat obesity. Herein, adipose-targeting ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) composed of an adipose-targeting peptide, Fe3+, a photosensitizer (protoporphyrin IX), and a browning agent (baicalin) are introduced. Pep-PPIX-Baic NPs have been designed to simultaneously enhance the photodynamic effect and induce browning. After intravenous injection in obese mice, the hybrid nanoparticles can specifically accumulate in white adipose tissues, especially those rich in blood supply, and drive adipose reduction owing to the synergy of the PDT effect and baicalin browning induction. Overall, Pep-PPIX-Baic NPs exhibited superior anti-obesity potential through PDT synergistic with adipose browning induction. The designed multifunctional adipose-targeting hybrid nanoparticles present a prospective nanoplatform for obesity treatment.

H2O2-triggered "off/on signal" nanoparticles target P-selectin for the non-invasive and contrast-enhanced theranostics for arterial thrombosis.

Pathological coagulation within an injured artery and the subsequent cardiovascular complications, such as stroke and heart attack, greatly threaten human life. Inspired by the biochemical features of acute arterial thrombosis, such as abundant activated platelets and hydrogen peroxide (H2O2), we constructed platelet-targeted theranostic nanoparticles (CyBA/PFM NPs) with H2O2-triggered photoacoustic contrast enhancement and antithrombotic capabilities. CyBA/PFM NPs were designed to target platelet-rich clots via fucoidan segment within the carrier, which could be activated by H2O2 to produce fluorescent "CyOH" molecules, thus turning on the photoacoustic signal. CyBA/PFM NPs showed obvious amplification of fluorescence following incubation with fresh clots, exhibiting efficient scavenging ability of intracellular reactive oxygen species (ROS). In a FeCl3-induced mouse model of carotid thrombosis, CyBA/PFM NPs significantly amplified the photoacoustic contrast in thrombogenic tissues, effectively eliminated ROS within the occlusion site, and suppressed the thrombus formation, accompanied by a normalization of the soluble CD40L level. Given their accurate imaging potential, potent antithrombotic activities and acceptable biosafety, CyBA/PFM NPs hold strong potential as nanoscale theranostics for H2O2-correlated cardiovascular diseases. STATEMENT OF SIGNIFICANCE: In this study, we developed a platelet-targeted and H2O2-triggered nanosystem self-assembled from phenylboronated fucoidan/maltodextrin polymers and responsive near-infrared probes. The fucoidan segment within the carrier could facilitate the specific delivery of the therapeutic polymers and probes to the platelet-rich arterial thrombus. In a mouse model of FeCl3-induced arterial thrombosis, the system could be activated by H2O2 to produce fluorescent "CyOH" molecules, thus turning on the photoacoustic signal and specifically imaging thrombosed tissues. Besides, CyBA/PFM NPs significantly effectively eliminated ROS within the occlusion site and suppressed the thrombus formation. Given their theranostic potential and acceptable biosafety, this system has great potential for H2O2-correlated cardiovascular diseases.

A biotin-modified and H2O2-activatable theranostic nanoplatform for enhanced photothermal and chemical combination cancer therapy.

Although synergistic effects of photothermal therapy (PTT) and chemotherapy for cancer have been extensively investigated in previous studies, more potential strategies need to be exploited to alleviate severe adverse effects. In this study, a biotin-modified and activatable nanotheranostic system is developed. This system (BPSP/DOX-CyBA) composed of H2O2-sensitive thioketal (TK) linker, hydrophilic biotin-decorated polyethylene glycol (PEG) segment, hydrophobic polycaprolactone (PCL) segment, could self-assemble into (99 ± 1.3) nm nanoparticles and co-deliver H2O2-triggered photosensitizer CyBA and cytotoxic drugs DOX to tumor site. In vitro, DOX and CyBA could release rapidly from nanoparticles, CyBA accumulation in the mitochondria causes mitochondrial damage, leading to mitochondrial dysfunctions,while rising the level of ROS in B16F10 cells, and further to promote the micells to trigger release. CyBA could be activated into CyOH and the photothermal therapy was turn "off" into "on". In BPSP/DOX-CyBA group, the local temperature within tumor reached 50 °C and cell apoptosis rate reached 68.6% under Laser irradiation (650 nm, 1 W/cm2). Fluorescence microscopy and flow cytometry analysis further demonstrated the better uptake efficiency on B16F10 cells with biotin decoration. In a mice B16F10 tumor model, the group with co-delivery CyBA and DOX had the best tumor retention effect, the maximal local temperature increasement and the minimum tumor growth with negligible side effects, suggesting the potential of BPSP/DOX-CyBA nanopalteform that synergistic photothermal therapy and chemotherapy and mitochondria damage as an effective melanoma treatment strategy.