Journal of Controlled Release最新文献

Herein, we synthesized and characterized gadolinium-based hyperbranched polymers, POADGd and PODGd, through RAFT polymerization as magnetic resonance imaging (MRI) contrast agents for detecting fibrosis. POADGd and PODGd contain biocompatible short-chain OEGMA to prolong blood circulation, and they can be decomposed in response to ROS after MRI examination to prevent potential accumulation. The relaxivities of POADGd and PODGd are 9.81 mM⁻¹ s⁻¹ and 9.58 mM⁻¹ s⁻¹ respectively, which are significantly higher than that of DTPA-Gd, a clinically used agent (3.74 mM⁻¹ s⁻¹). In comparison with PODGd, POADGd can specifically target allysine in fibrosis tissues through its oxyamine groups. Therefore, it displays a sharp spatial resolution and a high signal-to-noise ratio in the liver and lung fibrosis tissue at a field strength of 3.0 T or 7.0 T, and the morphology of these fibrosis tissues is accurately delineated. Our MRI diagnosis results based on POADGd are highly aligned with those from pathological examinations, while MRI diagnosis could avoid invasive biopsy. In addition, POADGd shows excellent biosafety and low toxicity. Therefore, POADGd could be applied to non-invasively and accurately diagnose liver and lung fibrosis diseases.

Lipid nanoparticles (LNPs) have recently been used as nanocarriers in drug delivery systems for nucleic acid drugs. Their practical applications are currently primarily limited to the liver and specific organs. However, altering the type and composition ratio of phospholipids improves their distribution in organs other than the liver, such as the spleen and lungs. This study aimed to elucidate the effects of LNP components and particle size on in vivo distribution through systemic circulation to pancreatic islets to achieve better targeting of islets, which are a fundamental therapeutic target for diabetes. Fluorescence-labeled LNPs were prepared using three phospholipids: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), with particle sizes of 30–160 nm (diameter) using a microfluidic device. Baffled-structured iLiNP devices with adjusted flow-rate ratios and total flow rates were used. After the intravenous administration of LNPs to C57BL/6 J mice, the distribution of each LNP type to the major organs, including the pancreas and pancreatic islets, was compared using ex vivo fluorescence imaging and observation of pancreatic tissue sections. DSPC-LNPs- and DOPE-LNPs showed the highest distribution in the spleen and liver, respectively. In contrast, the DOPC-LNPs showed the highest distribution in the pancreas and the lowest distribution in the liver and spleen. In addition, smaller particles showed better distribution throughout the pancreas. The most significant LNP distribution in the islets was observed for DOPC-LNPs with a particle size of 160 nm. Furthermore, larger LNPs tended to be distributed in the islets, whereas smaller LNPs tended to be distributed in the exocrine glands. DOPC-LNPs were distributed in the islets at all cholesterol concentrations, with a high distribution observed at >40% cholesterol and > 3% PEG and the distribution was higher at 24 h than at 4 h. Thus, LNP composition and particle size significantly affected islet distribution characteristics, indicating that DOPC-LNPs may be a drug delivery system for effectively targeting the pancreas and islets.

Radiotherapy widely applied for local tumor therapy in clinic has been recently reinvigorated by the discovery that radiotherapy could activate systematic antitumor immune response. Nonetheless, the endogenous radio-immune effect is still incapable of radical tumor elimination due to the prevention of immune cell infiltration by the physical barrier in tumor microenvironment (TME). Herein, an engineered Salmonella secreting nattokinase (VNP^NKase) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNP^NKase enriches at the tumor site after systemic administration, continuously secreting abundant NKase to degrade fibronectin, dredge the extracellular matrix (ECM), and inactivate cancer-associated fibroblasts (CAFs). The VNP^NKase- dredged TME facilitates the infiltration of CD103⁺ dendritic cells (DCs) and thus the presentation of tumor-associated antigens (TAAs) after radiotherapy, recruiting sufficient CD8⁺ T lymphocytes to specifically eradicate localized tumors. Moreover, the pre-treatment of VNP^NKase before radiotherapy amplifies the abscopal effect and achieves a long-term immune memory effect, preventing the metastasis and recurrence of tumors. Our research suggests that this strategy using engineered bacteria to breach tumor physical barrier for promoting immune cell infiltration possesses great promise as a translational strategy to enhance the effectiveness of radio-immunotherapy in treating solid tumors.

As a key pathological feature of pancreatic ductal adenocarcinoma(PDAC), the dense extracellular matrix(ECM) limits the penetration of chemotherapy drugs and is involved in the formation of immunosuppressive microenvironment. Meanwhile, clinical practice has shown that the treatment strategy for ECM should consider its restriction of tumor cell metastasis, and the need for in-depth chemotherapy without destroying ECM is proposed. STAT3 inhibitors have been reported to regulate tumor microenvironment including interrupt the form of ECM. Therefore, we designed and established a micelle system MP@HA with in vivo targeting and responsive drug release function co-loading gemcitabine monophosphate and STAT3 inhibitor silibinin. The hyaluronic acid on the surface of the micelle can bind specifically to the CD44 molecule on the surface of tumor cells and help micelles accumulate at the tumor site. The nitroimidazole used to modify the polymeric skeleton can make the micellar structure collapse in response to hypoxia reduction conditions in the tumor environment, and release silibinin to widely regulate STAT3 molecules in the PDAC microenvironment. The polymer fragment attached with gemcitabine monophosphate can penetrate deep into PDAC tumors due to its small size and positive charge exposed, achieving deep chemotherapy. This research indicates a promising micelle system meeting complicated demands proposed in PDAC treatment to improve antitumor efficacy.

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the “cold” hepatic tumor microenvironment that acts as T cell “traps” for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a “hot” phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4⁺ T cells, and rejuvenation of dendritic cells along with CD8⁺ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of “cold” tumors and their liver metastases.

Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.

Precisely co-delivering antigens and immunosuppressants via nano/microcarriers to antigen-presenting cells (APCs) to induce antigen-specific immune tolerance represents a highly promising strategy for treating or preventing autoimmune diseases. The physicochemical properties of nano/microcarriers play a pivotal role in regulating immune function, with particle size and surface charge emerging as crucial parameters. In particular, very few studies have investigated micron-scale carriers of antigens. Herein, various nanoparticles and microparticles (NPs/MPs) with diverse particle sizes (ranging from 200 nm to 5 μm) and surface charges were prepared. Antigen peptides (MOG35–55) and immunosuppressants were encapsulated in these particles to induce antigen-specific immune tolerance. Two emulsifiers, PVA and PEMA, were employed to confer different surface charges to the NPs/MPs. The in vitro and in vivo studies demonstrated that NP/MP-PEMA could induce immune tolerance earlier than NP/MP-PVA and that NP/MP-PVA could induce immune tolerance more slowly and sustainably, indicating that highly negatively charged particles can induce immune tolerance more rapidly. Among the different sizes and charged particles tested, 200-nm-NP-PVA and 3-μm-MP-PEMA induced the greatest immune tolerance. In addition, the combination of NPs with MPs can further improve the induction of immune tolerance. In particular, combining 200 nm-NP-PVA with 3 μm-MP-PEMA or combining 500 nm-NP-PEMA with 3 μm-MP-PVA had optimal therapeutic efficacy. This study offers a new perspective for treating diseases by combining NPs with MPs and applying different emulsifiers to prepare NPs and MPs.

mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8⁺ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations.

Convincing evidence suggests that aberrant gut microbiota changes play a critical role in the progression and pathogenesis of inflammatory bowel disease (IBD). Probiotic therapeutic interventions targeting the microbiota may provide alternative avenues to treat IBD, but currently available probiotics often suffer from low intestinal colonization and limited targeting capability. Here, we developed azido (N₃)-modified Prussian blue nanozyme (PB@N₃) spatio-temporal guidance enhances the targeted colonization of probiotics to alleviate intestinal inflammation. First, clickable PB@N₃ targets intestinal inflammation, simultaneously, it scavenges reactive oxygen species (ROS). Subsequently, utilizing “click” chemistry to spatio-temporally guide targeted colonization of dibenzocyclooctyne (DBCO)-modified Lactobacillus reuteri DSM 17938 (LR@DBCO). The “click” reaction between PB@N₃ and LR@DBCO has excellent specificity and efficacy both in vivo and in vitro. Despite the complex physiological environment of IBD, “click” reaction can prolong the retention time of probiotics in the intestine. Dextran sulfate sodium (DSS)-induced colitis mice model, demonstrates that the combination of PB@N₃ and LR@DBCO effectively mitigates levels of ROS, enhances the colonization of probiotics, modulates intestinal flora composition and function, regulates immune profiles, restores intestinal barrier function, and alleviates intestinal inflammation. Hence, PB@N₃ spatio-temporal guidance enhances targeted colonization of LR@DBCO provides a promising medical treatment strategy for IBD.

Ischemic stroke-induced mitochondrial dysfunction in the blood-brain barrier-forming brain endothelial cells (BECs) results in long-term neurological dysfunction post-stroke. We previously reported data from a pilot study where intravenous administration of human BEC (hBEC)-derived mitochondria-containing extracellular vesicles (EVs) showed a potential efficacy signal in a mouse middle cerebral artery occlusion (MCAo) model of stroke. We hypothesized that EVs harvested from donor species homologous to the recipient species (e.g., mouse) may improve therapeutic efficacy, and therefore, use of mouse BEC (mBEC)-derived EVs may improve post-stroke outcomes in MCAo mice.

We investigated potential differences in the mitochondria transfer of EVs derived from the same species as the recipient cell (mBEC-EVs and recipient mBECs or hBECs-EVs and recipient hBECs) vs. cross-species EVs and recipient cells (mBEC-EVs and recipient hBECs or vice versa). Our results showed that while both hBEC- and mBEC-EVs transferred EV mitochondria, mBEC-EVs outperformed hBEC-EVs in increasing ATP levels and improved recipient mBEC mitochondrial function via increasing oxygen consumption rates. mBEC-EVs significantly reduced brain infarct volume and neurological deficit scores compared to vehicle-injected MCAo mice. The superior therapeutic efficacy of mBEC-EVs in MCAo mice support the continued use of mBEC-EVs to optimize the therapeutic potential of mitochondria-containing EVs in preclinical mouse models.