Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation.

Microwave ablation (MWA) is a frequently adopted regional therapy for treating hepatocellular carcinoma (HCC) in clinic. However, incomplete microwave ablation (IMWA) is often inevitable due to the restraint of ablating large tumors or tumors in special locations, resulting in a high recurrence rate of HCC. Moreover, the most promising immune checkpoint blockade (ICB)-based immunotherapy is raising hindered by the toxicity and insufficient immune response. To overcome these barriers, we conjugate small nanovesicle (smDV)-derived from matured dendritic cells (mDCs) with anti-CTLA-4 antibody (smDV-aCTLA-4) using a metabolic tagging technology, which could trigger the infiltration of cytotoxic T cells (CTLs) and adopted tumor-infiltrating lymphocytes (TILs) in residual HCC after IMWA. In HCC microenvironment, the administration of smDV-aCTLA-4 could promote antigen presentation and immune checkpoint suppression to activate CTLs and improve the safety of anti-CTLA-4 antibody. Moreover, the anti-tumor efficacy of CTLs elicited by smDV-aCTLA-4 could also be further enhanced by anti-programmed death 1 (aPD-1) antibody. In addition, compared to the adoptive TILs therapy, the treatment using smDV-aCTLA-4-bonded TILs (smDV-aCTLA-4@TILs) could promote the proliferation and infiltration of cytotoxic TILs in residual HCC after IMWA. Our results clearly evidences the potency of a new type of engineered DC nanovesicles in reducing HCC recurrence after IMWA.

Mesoporous Polydopamine Nanotherapeutics for MRI-Guided Cancer Photothermal and Anti-Inflammatory Therapy.

Background: As a burgeoning cancer treatment modality, photothermal therapy (PTT) has shown robust anti-tumor effects. However, it still faces numerous challenges, such as triggering an inflammatory response and potentially increasing the risk of cancer recurrence. To address these concerns, integration of PTT with anti-inflammatory therapies presents a promising approach to enhance the efficacy of cancer treatment and meanwhile reduce the risk of recurrence. Methods: In this study, Gd3+ was first chelated with dopamine to create Gd-DA chelates, and then the mesoporous dopamine nanoparticles MX@Arg-Gd-MPDA (MAGM NPs) were synthesized by combining arginine (Arg) and the anti-inflammatory medication meloxicam (MX). The photothermal properties of MAGM NPs were then defined and examined; the in vivo MRI imaging effect, as well as MAGM NPs' anti-cancer and anti-inflammatory efficiency, were tested in a mouse model of breast cancer. Results: The incorporation of Arg doping into MAGM NPs was intended to boost its photothermal conversion efficiency and reactive oxygen species (ROS) scavenging ability. Additionally, synergizing with the anti-inflammatory agent meloxicam (MX) within the nanoparticles aimed to enhance the anti-inflammatory effect following photothermal therapy. Furthermore, gadolinium ions (Gd3+) were chelated into the nanostructure to enable precise T1-T2 dual-mode magnetic resonance imaging (MRI) of the intratumor accumulation profile. This imaging capability was leveraged to guide the implementation of photothermal therapy. Animal experiments demonstrated that MAGM NPs exerted a notable anticancer effect in a 4T1 breast cancer mouse model, under the precise guidance of MRI.

Enzyme-responsive microgel with controlled drug release, lubrication and adhesion capability for osteoarthritis attenuation.

The treatment of osteoarthritis (OA) remains challenging due to the narrow therapeutic window and rapid clearance of therapeutic agents, even with intra-articular administration, resulting in a low treatment index. Recent advancements in local drug delivery systems have yet to overcome the issues of uncontrolled burst release and short retention time, leading to suboptimal OA treatment outcome. Herein, we developed a methacrylate-crosslinking hyaluronic acid (HA) microgel (abbreviated as CXB-HA-CBP) that covalently conjugates the anti-inflammatory drug celecoxib (CXB) via a metalloproteinase-2 (MMP-2)-responsive peptide linker (GGPLGLAGGC) and a collagen II binding peptide (WYRGRLC). The GGPLGLAGGC linker is specifically cleaved by the overexpressed MMP-2 enzyme within the OA joint, enabling the sustained and on-demand release of CXB entity. The synergistic action of CXB and HA effectively inhibited macrophage activation and reduced the production of pro-inflammatory cytokines, protecting chondrocytes from damage. Furthermore, the collagen II peptide introduced on the microgel surface enabled a cartilage-binding function to form an artificial lubrication microgel layer on the cartilage surface to reduce cartilage wear. The CXB-HA-CBP microgel showed an extended retention time of up to 18 days in the affected joint, leading to an effective OA treatment in rats. This sophistically designed microgel, characterized by the prolonged retention time, sustained drug delivery, and enhanced lubrication, presents a promising biomedicine for OA treatment. STATEMENT OF SIGNIFICANCE: A new methacrylate-crosslinking hyaluronic acid (HA) microgel, covalently conjugated with the celecoxib (CXB)-GGPLGLAGGC and the collagen II binding peptide (CBP, peptide sequence: WYRGRLC), was developed. The overexpressed MMP-2 in OA joint cleaved the GGPLGLAGGC linker to trigger the CXB moiety release. Besides, the CBP on the surface of microgels enabled a cartilage-attaching ability, resulting in a prolonged retention time and an improved lubrication property in joint. This advanced drug-loading microgel remarkably reduced macrophage activation and pro-inflammation cytokine production, while protecting the chondrocytes via a dual action of CXB and HA. This study demonstrated that the enzyme-responsive drug-loading microgel could serve as an platform to efficiently attenuate osteoarthritis.

Tertiary lymphoid structure formation induced by LIGHT-engineered and photosensitive nanoparticles-decorated bacteria enhances immune response against colorectal cancer.

Tertiary lymphoid structures (TLSs) are known to enhance the prognosis of patients with colorectal cancer (CRC) by fostering an immunologically active tumor microenvironment (TME). Inducing TLS formation therapeutically holds promise for treating immunologically cold CRC, though it poses technical challenges. Here, we design and fabricate a photosensitive bacterial system named E@L-P/ICG. This system is engineered bacteria internally loaded with the cytokine LIGHT and surface-modified with PLGA/ICG nanoparticles (P/ICG NPs). Once accumulated in orthotopic colonic tumors in mice, E@L-P/ICG generates a mild photothermal effect under laser irradiation due to the photosensitive P/ICG NPs. This photothermal effect triggers the self-rupture of E@L-P/ICG and the death of surrounding tumor cells to release adjuvants and antigens, respectively, which in turn synergistically activate the adaptive immune responses. Furthermore, the cytokine LIGHT released from ruptured E@L-P/ICG stimulates the generation of high endothelial vessels (HEVs), promoting lymphocyte recruitment within the TME. These mechanisms lead to the TLS formation in CRC, which further boosts adaptive immune responses through effective infiltration of T cells and B cells, resulting in effectively inhibited tumor growth and extended survival of mice. Our study shows the potential of the E@L-P/ICG system in photosensitively inducing the TLS formation to treat CRC in clinic.

Acidity-Actuated Polymer/Calcium Phosphate Hybrid Nanomotor (PCaPmotor) for Penetrating Drug Delivery and Synergistic Anticancer Immunotherapy.

Tumor acidity-driven nanomotors may offer robust propulsion for tumor-specific penetrating drug delivery. Herein, an acidity-actuated poly(amino acid) calcium phosphate (CaP) hybrid nanomotor (PCaPmotor) was designed, using a mPEG-PAsp-PPhe@THZ531 micelle (Poly@THZ) for CaP mineralization accompanied by αPD-L1 antibody encapsulation. Dissolution of the CaP layer in an acidic tumor environment gave off heat energy to propel the nanomotor to augment the cellular uptake and penetration into deeply seated cancer cells while facilitating αPD-L1 release. THZ531 delivered by the PCaPmotor inhibited CDK12 and its down-streamed phosphorylation of RNAP-II to increase the cancer immunogenicity events such as the DNA damage, cell apoptosis, immunogenic cell death, lysosomal function disturbance, and MHC-I upregulation. THZ531 and αPD-L1 cosupplied by PCaPmotor significantly increased the frequency of DCs maturation and intratumoral infiltration of CTLs, but the two free drugs did not. Consequently, the PCaP@THZ/αPD-L1 nanomotor resulted in synergistic anticancer immunotherapy in mice. This acid-actuated PCaPmotor represented a new paradigm for penetrating drug delivery.

Black phosphorus quantum dots prevent atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases such as coronary heart disease. Black phosphorus quantum dots (BPQDs) are a novel nanomaterial with good optical properties and biocompatibility, which was applied in the treatment of AS in mice, with good results shown in our previous study. In this study, BPQDs were injected into high-fat diet-fed apolipoprotein E knockout mice as a preventive drug for 12 weeks. Simvastatin, a classic preventive drug for AS, was used as a control to verify the preventive effect of BPQDs. The results showed that after preventive treatment with BPQDs, the plaque area in mice was significantly reduced, the vascular elasticity was increased, and serum lipid levels were significantly lower than those in the model group. To explore the mechanism, macrophages were induced to become foam cells using oxidized low-density lipoprotein. We found that BPQDs treatment could increase cell autophagy, thereby regulating intracellular lipid metabolism. Taken together, these data revealed that BPQDs may serve as a functional drug in preventing the development of AS.

19F MRI/CEUS Dual Imaging-Guided Sonodynamic Therapy Enhances Immune Checkpoint Blockade in Triple-Negative Breast Cancer.

Treatment of highly aggressive triple-negative breast cancer (TNBC) in the clinic is challenging. Here, a liposome nanodrug (LP@PFH@HMME) integrating imaging agents and therapeutic agents for bimodal imaging-guided sonodynamic therapy (SDT) is developed, which boosted immunogenicity to enable potent immunotherapy via immune checkpoint blockade (ICB) in TNBC. In the acidic tumor microenvironment (TME), LP@PFH@HMME undergoes "nano-to-micro" transformation due to a pH-responsive lipid fusion, which makes droplets much more sensitive to ultrasound (US) in contrast-enhanced ultrasound (CEUS) and SDT studies. The nanodrug demonstrates robust bimodal imaging ability through fluorine-19 magnetic resonance imaging (19F MRI) and CEUS bimodal imaging, and it exhibits excellent solubility in aqueous solution with relatively high 19F content and desirable long transverse relaxation time (T2 = 1.072 s), making it suitable for high-performance 19F MRI, in addition to effective accumulation of nanodrugs after tail vein injection. Thus, 19F MRI/CEUS dual imaging is achievable to show adequate time points for US irradiation of tumor sites to induce highly effective SDT, which produces abundant reactive oxygen species (ROS) triggering immunogenic cell death (ICD) to assist ICB-based immunotherapy. The combination treatment design of sonodynamic therapy with immunotherapy effectively inhibited TNBC growth and recurrence, highlighting the promise of multifunctional nanodrugs in treating TNBC.

Blood Brain Barrier-Crossing Delivery of Felodipine Nanodrug Ameliorates Anxiety-Like Behavior and Cognitive Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.

Manganese oxide-constructed multifunctional biomimetic nanovaccine for robust tumor-specific T cell priming and chemodynamic therapy.

The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy. Compared with the nanovaccines coated with the single cell membrane, the MP@RHM nanovaccine highly efficiently activates both DCs and T cells to boost tumor-specific T cell, owing to the synergistic effects of abundant damage-associated molecular patterns, Mn2+, and T cell-stimulating moieties. Upon peritumoral injection, the MP@RHM nanovaccine targets both the tumor site for focused chemodynamic therapy and the lymph nodes for robust tumor-specific T cell priming, thereby achieving highly efficient chemodynamic immunotherapy. Moreover, as a preventive cancer nanovaccine, MP@RHM generates strong immunological memory to inhibit postoperative tumor metastasis and recurrence. Our study findings highlight a promising approach to construct a multifunctional biomimetic nanovaccine for personalized chemodynamic immunotherapy against solid tumors.

Light-inducible nanodrug-mediated photodynamic and anti-apoptotic synergy for enhanced immunotherapy in triple-negative breast cancer.

Triple negative breast cancer (TNBC) exhibits limited responsiveness to immunotherapy owing to its immunosuppressive tumor microenvironment (TME). Here, a reactive oxygen species (ROS)-labile nanodrug encapsulating the photosensitizer Ce6 and Bcl-2 inhibitor ABT-737 was developed to provoke a robust immune response via the synergistic effect of photodynamic therapy (PDT) and the reversal of apoptosis resistance. Upon exposure to first-wave near-infrared laser irradiation, the generated ROS triggers PEG cleavage, facilitating the accumulation of the nanodrug at tumor region and endocytosis by tumor cells. Further irradiation leads to the substantial generation of cytotoxic ROS, initiating an immunogenic cell death (ICD) cascade, which prompts the maturation of dendritic cells (DCs) as well as the infiltration of T cells into the tumor site. Meanwhile, Bcl-2 inhibition counteracts apoptosis resistance, thereby amplifying PDT-induced ICD and bolstering antitumor immunity. As a result, the ROS-sensitive nanodrug demonstrates a potent inhibitory effect on tumor growth.

Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System.

Effective antitumor immunotherapy depends on evoking a cascade of cancer-immune cycles with lymph nodes (LNs) as the initial sites for activating antitumor immunity, making drug administration through the lymphatic system highly attractive. Here, we describe a nanomedicine with dual responsiveness to pH and enzyme for a programmed activation of antitumor immune through the lymphatic system. The proposed nanomedicine can release the STING agonist diABZI-C2-NH2 in the LNs' acidic environment to activate dendritic cells (DCs) and T cells. Then, the remaining nanomedicine hitchhikes on the activated T cells (PD-1+ T cells) through binding to PD-1, resulting in an effective delivery into tumor tissues owing to the tumor-homing capacity of PD-1+ T cells. The enzyme matrix metalloproteinase-2 (MMP-2) being enriched in tumor tissue triggers the release of PD-1 antibody (aPD-1) which exerts immune checkpoint blockade (ICB) therapy. Eventually, the nanomedicine delivers a DNA methylation inhibitor GSK-3484862 (GSK) into tumor cells, and then the latter combines with granzyme B (GZMB) to trigger tumor cell pyroptosis. Consequently, the pyroptotic tumor cells induce robust immunogenic cell death (ICD) enhancing the DCs maturation and initiating the cascading antitumor immune response. Study on a 4T1 breast tumor mouse model demonstrates the prominent antitumor therapeutic outcome of this nanomedicine through creating a positive feedback loop of cancer-immunity cycles including immune activation in LNs, T cell-mediated drug delivery, ICB therapy, and tumor cell pyroptosis-featured ICD.

Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

MnO2/Ce6 microbubble-mediated hypoxia modulation for enhancing sono-photodynamic therapy against triple negative breast cancer.

Sono-photodynamic therapy (SPDT) has emerged as a promising treatment modality for triple negative breast cancer (TNBC). However, the hypoxic tumor microenvironment hinders the application of SPDT. Herein, in this study, a multifunctional platform (MnO2/Ce6@MBs) was designed to address this issue. A sono-photosensitizer (Ce6) and a hypoxia modulator (MnO2) were loaded into microbubbles and precisely released within tumor tissues under ultrasound irradiation. MnO2in situ reacted with the excess H2O2 and H+ and produced O2 within the TNBC tumor, which alleviated hypoxia and augmented SPDT by increasing ROS generation. Meanwhile, the reaction product Mn2+ was able to achieve T1-weighted MRI for enhanced tumor imaging. Additionally, Ce6 and microbubbles served as a fluorescence imaging contrast agent and a contrast-enhanced ultrasound imaging agent, respectively. In in vivo anti-tumor studies, under the FL/US/MR imaging guidance, MnO2/Ce6@MBs combined with SPDT significantly reversed tumor hypoxia and inhibited tumor growth in 4T1-tumor bearing mice. This work presents a theragnostic system for reversing tumor hypoxia and enhancing TNBC treatment.

Correction: MnO2/Ce6 microbubble-mediated hypoxia modulation for enhancing sono-photodynamic therapy against triple negative breast cancer.

Correction for 'MnO2/Ce6 microbubble-mediated hypoxia modulation for enhancing sono-photodynamic therapy against triple negative breast cancer' by Ping Li et al., Biomater. Sci., 2024, https://doi.org/10.1039/d3bm00931a.

Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer.

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Anchoring Microbubbles on Cerebrovascular Endothelium as a New Strategy Enabling Low-Energy Ultrasound-Assisted Delivery of Varisized Agents Across Blood-Brain Barrier.

The protective blood-brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect. Here, we constructed a novel perfluoropropane-loaded microbubble, termed ApoER-Pep-MB, which possessed a siloxane bonds-crosslinked surface to increase the microbubble stability against turbulence in blood circulation and was decorated with binding peptide for apolipoprotein E receptor (ApoER-Pep). The microbubble with tailor-made micron size (2 µm) and negative surface charge (-30 mV) performed ApoER-mediated binding rather than internalization into brain capillary endothelial cells. Consequently, the microbubble accumulated on the brain microvessels, based on which even a low-energy ultrasound with less safety risk than FUS, herein diagnostic ultrasound (DUS), could create a strong cavitation effect to open the BBB. Evans Blue and immunofluorescence staining studies demonstrated that the DUS-triggered cavitation effect not only temporarily opened the BBB for 2 h but also caused negligible damage to the brain tissue. Therefore, various agents, ranging from small molecules to nanoscale objects, can be efficiently delivered to target regions of the brain, offering tremendous opportunities for the treatment of brain diseases.

Nanodrug regulates ROS homeostasis via enhancing fatty acid oxidation and inhibiting autophagy to overcome tumor drug resistance.

The treatment of drug-resistant tumors poses a significant challenge in the field of tumor therapy. Disrupting the homeostasis of reactive oxygen species (ROS) within tumor cells may represent a pivotal strategy for overcoming the prevalent issue of drug resistance. However, the restricted sustainability of ROS generation and the increased autophagy capacity exhibited by tumor cells hinder the application of ROS-based therapies. In this study, we developed liposome nanoparticles (Ato/CQ@L) for co-encapsulation of atorvastatin (Ato), an activator of AMP-activated protein kinase (AMPK), and chloroquine (CQ), an autophagy inhibitor. Upon internalization by tumor cells, Ato upregulated carnitine palmitoyltransferase 1(CPT1) concentration and promoted fatty acid oxidation (FAO) within the tumor cells. The process of FAO coupled with an abundance of fatty acid substrates, facilitates a sustained generation of ROS production. Concurrently, a positive feedback loop is established between escalated concentration of ROS and AMPK protein levels, resulting in a persistent elevation in ROS levels. In addition, CQ disrupted lysosomes, leading to an increased lysosomal pH and reducing autophagy in tumor cells. In both in vivo and in vitro experiments, the Ato/CQ@L treatment group exhibited a considerable enhancement in tumor cell apoptosis, validating the efficacy of this combined therapy. In summary, the combined therapy involving Ato and CQ addresses the inherent limitations of conventional ROS therapy, which include insufficient ROS production and increased autophagy. This approach holds significant potential as a treatment strategy for drug-resistant triple-negative breast cancer.

A nanodrug simultaneously inhibits pancreatic stellate cell activation and regulatory T cell infiltration to promote the immunotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer.