Journal of Controlled Release最新文献

Reactive oxygen species (ROS)-based cancer treatment leverages their strong oxidizing properties to damage cellular components, inducing apoptosis and eliminating tumours. In comparison with ROS, reactive nitrogen species (RNS) demonstrate enhanced nitrification and oxidation capabilities, which exert more significant damage on tumour cells. Herein, we described a 980-nm laser-responsive prodrug nanosystem (RCLA) consisted of rare earth nanoparticles (RENPs, NaYF₄:Yb, 20 %Er@NaYF₄:Yb) and Ce-UiO-66-NH₂, which enables the controlled release of L-arginine and efficient production of RNS through cascade enzymatic catalysis. After the modulation of doping Er³⁺ concentrations, the laser-responsive RCLA not only exhibited excellent NIR-II fluorescence imaging, but also possessed Förster energy transfer to enhance cascade enzymatic activity. In addition, RCLA show high-efficient catalase- and oxidase-like activity to induce the generated O₂ to convert into ROS. Then, the excessive ROS cleaves the ROS-sensitive thioketal bond in RCLA to release free L-arginine, and further reacts with L-arginine to subsequently generate RNS. Finally, RNA sequencing analysis reveals that RCLA profoundly affects the normal biological functions of tumour cells by inducing oxidative stress and activating apoptosis-related pathways. Combined with the anti-tumour activity of RCLA in vitro and in vivo, this nanozyme system provides an efficient and precise strategy for synergistic cancer therapy.

Gas therapy, an emerging and promising tumor treatment strategy, has garnered increasing research interest. Recent attention has focused on gas signaling molecules due to their unique biological effects and potent immunomodulatory activities. With rapid advances in nanotechnology, diverse gas-generating nanoplatforms have been developed to augment cancer immunotherapy. This review first elucidates the mechanisms by which bioactive gas molecules amplify anti-tumor immunity and outlines design strategies for constructing gas-generating nanoplatforms. Thereafter, we summarize the applications of these nanoplatforms in gas-enhanced tumor immunotherapy, highlighting key bioactive gas signal molecules, including hydrogen sulfide (H₂S), nitric oxide (NO), carbon monoxide (CO), and hydrogen (H₂). Finally, the biosafety profiles of these systems and prospect future opportunities and challenges are discussed.

Clostridioides difficile infection (CDI) is strongly linked to disruptions in gut microbial homeostasis. Although conventional antibiotics effectively inhibit C. difficile proliferation, they frequently fail to reestablish microbial equilibrium, thereby constraining therapeutic outcomes. Probiotic therapy seeks to modulate gut microecology by replenishing beneficial microorganisms; however, its clinical efficacy is hindered by poor gastrointestinal survivability, limited colon-targeted engraftment, and inadequate suppression of C. difficile virulence determinants. To address these challenges, we developed a polysaccharide-based hydrogel platform (HF), named BA@HF-PDAT, designed for the synergistic co-delivery of Bifidobacterium adolescentis (BA) and polydopamine-thymol nanoparticles (PDA-TH NPs). HF-mediated encapsulation substantially enhances probiotic viability, facilitates colon- and inflammation-targeted controlled release, and promotes bacterial engraftment. Concurrently, PDA-TH effectively inhibits C. difficile virulence determinants, synergistically amplifying probiotic therapeutic potential. In vitro and in vivo analyses reveal that BA@HF-PDAT facilitates intestinal repair and mitigates apoptosis through Wnt/β-catenin signaling, exerts potent anti-inflammatory and antioxidant activities, and restores gut microbial composition and metabolic function, thereby effectively ameliorating CDI-induced colitis in murine models. Comparative studies further indicate that BA@HF-PDAT achieves superior therapeutic efficacy compared with vancomycin treatment. Collectively, this integrated co-delivery platform constitutes a promising and translational therapeutic strategy for CDI management.

Despite the crucial role of natural killer (NK) cells in initiating antitumor immune circuits, their efficacy is limited by tumor immune evasion mechanisms, including low surface density or proteolytic shedding of activating ligands and immunosuppression. Here, we constructed a bioorthogonal truncated NKG2D (natural killer group 2, member D) ligand-based nano-igniter (ZIL15-D-trMULT1) to synchronously enhance NK cell recognition and function, thereby igniting antitumor immune circuits. This system incorporates a truncated NKG2D ligand (trMULT1) lacking the cleavable α3 domain while retaining the NKG2D-binding α1/α2 domains, conjugated to dibenzocyclooctyne (DBCO) for bioorthogonal tagging of azide-modified tumor cells. Concurrently, interleukin-15 (IL-15) was encapsulated within zeolitic imidazolate frameworks (ZIF-8) for responsive release, sustaining NK cell function and upregulating NKG2D receptor expression. This synergistic design created a positive feedback loop for NK cell recognition and activation. Consequently, this strategy suppressed multiple tumor types and improved the immune microenvironment. Mechanistically, both innate and adaptive immunity were mobilized by orchestrating crosstalk between dendritic cells and T cells, facilitated by NK cell-derived chemokine secretion. In combination with anti-PD-1 antibody, ZIL15-D-trMULT1 induced durable immune memory, restraining distal tumor growth and lung metastasis. Our work unveils a self- sustaining immune circuit triggered by NK cells through upregulating the un-cleavable NKG2D ligand density, providing a robust strategy against solid tumors.

Disrupting mitochondrial metabolism and reactivating antitumor immunity offers a compelling strategy to enhance therapeutic outcomes in glioblastoma (GBM). Here, we report a mitochondria-targeting nanoplatform that integrates GBM-selective delivery, metabolic disruption, and immune activation for synergistic GBM therapy. The nanoplatform co-encapsulates L820-a conjugate of lonidamine (LND) and IR820 with mitochondrial affinity-and the immunomodulator TP5 into a ZIF-8 framework, which is coated with H-ferritin (HFn) for TfR1-mediated blood-brain barrier (BBB) penetration and GBM targeting. After endocytosis and GBM-specific, acid-triggered degradation, L820 accumulates in mitochondria and causes profound mitochondrial dysfunction, including membrane potential collapse, ATP depletion, and AMPK activation. Concurrently, Zn²⁺ released from ZIF-8 suppresses GLUT1 and HIF-1α, impairing glycolysis and reducing CD47 expression. These dual metabolic stresses induce mitochondrial DNA (mtDNA) release and activate the cGAS-STING pathway, promoting type I interferon production and immunogenic cell death. TP5 enhances T cell activation while suppressing Tregs, further remodeling the GBM immune microenvironment. This mitochondria-focused strategy achieves potent metabolic interference and immune reprogramming for effective GBM treatment.