Mild magnetic hyperthermia-activated immuno-responses for primary bladder cancer therapy.

Surgical intervention followed by chemotherapy is the principal treatment strategy for bladder cancer, which is hindered by significant surgical risks, toxicity from chemotherapy, and high rates of recurrence after surgery. In this context, a novel approach using mild magnetic hyperthermia therapy (MHT) for bladder cancer treatment through the intra-bladder delivery of magnetic nanoparticles is presented for the first time. This method overcomes the limitations of low magnetic thermal efficiency, inadequate tumor targeting, and reduced therapeutic effectiveness associated with the traditional intravenous administration of magnetic nanoparticles. Core-shell Zn-CoFe2O4@Zn-MnFe2O4 (MNP) nanoparticles were developed and further modified with hyaluronic acid (HA) to enhance their targeting ability toward tumor cells. The application of controlled mild MHT using MNP-HA at temperatures of 43-44 °C successfully suppressed the proliferation of bladder tumor cells and tumor growth, while also decreasing the expression levels of heat shock protein 70 (HSP70). Crucially, this therapeutic approach also activated the body's innate immune response involving macrophages, as well as the adaptive immune responses of dendritic cells (DCs) and T cells, thereby reversing the immunosuppressive environment of the bladder tumor and effectively reducing tumor recurrence. This study uncovers the potential immune-activating mechanism of mild MHT in the treatment of bladder cancer and confirms the effectiveness and safety of this strategy, indicating its promising potential for the clinical management of bladder cancer with a high tendency for relapse.

Nanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy.

Pro-tumoral macrophages in lung tumors present a significant challenge in immunotherapy. Here, we introduce a pH-responsive nanomedicine approach for activating anti-tumoral macrophages and dendritic cells. Using a layered double hydroxide nanosheet carrier, we co-deliver a T-type calcium channel inhibitor (TTA-Q6) and a CD47 inhibitor (RRX-001) into lung tumors. In the tumor acidic environment, TTA-Q6 is released, disrupting cancer cell calcium uptake, causing endoplasmic reticulum stress and inducing calreticulin transfer to the cell surface. Surface calreticulin activates macrophages and triggers dendritic cell maturation, promoting effective antigen presentation and therefore activating antitumor T cells. Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy.

Acid Neutralization and Immune Regulation by Calcium-Aluminum-Layered Double Hydroxide for Osteoporosis Reversion.

Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca2+ from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (Treg) and the deactivation of T helper 17 cells (TH17). Both in vitro and in vivo results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.

Low Colorectal Tumor Removal by E-Cadherin Destruction-Enabled Tumor Cell Dissociation.

Treatments for low colorectal cancer (CRC) remain a great challenge due to the heavy physical and psychological burdens of colostomy, strong drug toxicity in chemotherapy, and myelosuppression-/chemoradiation-related gastrointestinal symptoms. In this study, a highly biosafe and effective tumor cell dissociation-based low CRC treatment modality has been verified on both PDOs in vitro and colorectal tumor models in vivo. Notably, controllable EDTA release at the tumor sites was achieved by the LDH degradation in response to a slightly acidic microenvironment of low CRC tumors. Resultantly, the intratumoral E-cadherin for intercellular junctions of low CRC tumors was effectively destroyed via Ca2+ depletion by released EDTA from the interlayers, initiating remarkable tumor cell dissociation and resultant tumor disaggregation/removal via defecation. Dissociated tumor cells were prevailingly enveloped by LDH/EDTA, which prevented them from readhering to adjacent tissues, providing an unprecedented, efficient and safe therapeutic modality for low CRC, which will benefit patients suffering low CRC.

Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.

Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as reactive oxygen species in situ for cancer specific treatment by using exogenous-delivered catalysts such as Fenton agents. However, the overexpression of reductive glutathione and Cu-Zn superoxide dismutase in cancer cells will significantly counteract the therapeutic efficacy by reactive oxygen species-mediated oxidative damages. Additionally, the direct delivery of iron-based Fenton agents may arouse undesired detrimental effects such as anaphylactic reactions. In this study, instead of exogenously delivering Fenton agents, the endogenous copper ions from intracellular Cu-Zn superoxide dismutase have been employed as the source of Fenton-like agents by chelating the Cu ions from the superoxide dismutase using a common metal ion chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), followed by the TPEN-Cu(II) chelate reduction to TPEN-Cu(I) by reductive glutathione. Briefly, TPEN was loaded in a disulfide bond-containing link poly(acrylic acid) shell-coated hybrid mesoporous silica/organosilicate (MSN@MON) nanocomposite as a reductive glutathione-responsive nanoplatform, which features inter-related triple functions: intratumoral reductive glutathione-responsive link poly(acrylic acid) disruption and TPEN release; the accompanying reductive glutathione consumption and Cu-Zn superoxide dismutase deactivation by TPEN chelating Cu ions from this superoxide dismutase; and the Fenton reaction catalyzed by TPEN-Cu(I) chelate as a Fenton-like agent generated from TPEN-Cu(II) reduction by the remaining reductive glutathione in cancer cells, thereby cutting off the self-protection pathway of cancer cells under severe oxidation stress and ensuring cancer cell apoptosis by reactive oxygen species produced by the catalytic Fenton-like reactions. Such a nanocatalyst demonstrates excellent biosafety and augmented therapeutic efficacy by simultaneous nanocatalytic oxidative damage and intrinsic protection pathway breakage of cancer cells.

Efficient Gene Therapy of Pancreatic Cancer via a Peptide Nucleic Acid (PNA)-Loaded Layered Double Hydroxides (LDH) Nanoplatform.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors with extremely poor prognosis due to the later stage diagnosis when surgical resection is no longer applicable. Alternatively, the traditional gene therapy which drives pancreatic cancer cells into an inactive state and inhibiting the proliferation and metastasis, presents potentials to safely inhibit pancreatic cancer progression, but unfortunately has received limited success to date. Here, an efficient gene therapy of pancreatic cancer is shown via a peptide nucleic acid (PNA)-loaded layered double hydroxides (LDHs) nanoplatform. Compared with the traditional DNA- or RNA-based gene therapies, the gene therapy using PNA features great advantages in recognizing and hybridizing with the target mutant sequences to form PNA-DNA hybrids with significantly enhanced stability due to the absence of electrostatic repulsion, and the constrained flexibility of the polyamide backbone. Moreover, ultrasmall LDHs are engineered to load PNA and the obtained PNA-loaded LDH platform (LDHs/PNA) is capable of efficiently and selectively targeting the intranuclear mutant sequences thanks to the proton sponge effect. Treatments with LDHs/PNA demonstrate markedly inhibited growth of pancreatic cancer xenografts via a cancer cell proliferation suppression mechanism. The results demonstrate the great potentials of LDHs/PNA as a highly promising gene therapy agent for PDAC.

Combined Magnetic Hyperthermia and Immune Therapy for Primary and Metastatic Tumor Treatments.

Cancer immunotherapy shows promising potential in future cancer treatment but unfortunately is clinically unsatisfactory due to the low therapeutic efficacy and the possible severe immunotoxicity. Here we show a combined magnetic hyperthermia therapy (MHT) and checkpoint blockade immunotherapy for both primary tumor ablation and mimetic metastatic tumor inhibition. Monodispersed, high-performance superparamagnetic CoFe2O4@MnFe2O4 nanoparticles were synthesized and used for effective MHT-induced thermal ablation of primary tumors. Simultaneously, numerous tumor-associated antigens were produced to promote the maturation and activation of dendritic cells (DCs) and cytotoxic T cells for effective immunotherapy of distant mimetic metastatic tumors in a tumor-bearing mice model. The combined MHT and checkpoint blockade immunotherapy demonstrate the great potentials in the fight against both primary and metastatic tumors.

Ceria Nanoparticles Meet Hepatic Ischemia-Reperfusion Injury: The Perfect Imperfection.

The mononuclear phagocyte system (MPS, e.g., liver, spleen) is often treated as a "blackbox" by nanoresearchers in translating nanomedicines. Often, most of the injected nanomaterials are sequestered by the MPS, preventing their delivery to the desired disease areas. Here, this imperfection is exploited by applying nano-antioxidants with preferential liver uptake to directly prevent hepatic ischemia-reperfusion injury (IRI), which is a reactive oxygen species (ROS)-related disease. Ceria nanoparticles (NPs) are selected as a representative nano-antioxidant and the detailed mechanism of preventing IRI is investigated. It is found that ceria NPs effectively alleviate the clinical symptoms of hepatic IRI by scavenging ROS, inhibiting activation of Kupffer cells and monocyte/macrophage cells. The released pro-inflammatory cytokines are then significantly reduced and the recruitment and infiltration of neutrophils are minimized, which suppress subsequent inflammatory reaction involved in the liver. The protective effect of nano-antioxidants against hepatic IRI in living animals and the revealed mechanism herein suggests their future use for the treatment of hepatic IRI in the clinic.

Simultaneous Blood-Brain Barrier Crossing and Protection for Stroke Treatment Based on Edaravone-Loaded Ceria Nanoparticles.

Cerebral vasculature and neuronal networks will be largely destroyed due to the oxidative damage by overproduced reactive oxygen species (ROS) during a stroke, accompanied by the symptoms of ischemic injury and blood-brain barrier (BBB) disruption. Ceria nanoparticles, acting as an effective and recyclable ROS scavenger, have been shown to be highly effective in neuroprotection. However, the brain access of nanoparticles can only be achieved by targeting the damaged area of BBB, leading to the disrupted BBB being unprotected and to turbulence of the microenvironment in the brain. Nevertheless, the integrity of the BBB will cause very limited accumulation of therapeutic nanoparticles in brain lesions. This dilemma is a great challenge in the development of efficient stroke nanotherapeutics. Herein, we have developed an effective stroke treatment agent based on monodisperse ceria nanoparticles, which are loaded with edaravone and modified with Angiopep-2 and poly(ethylene glycol) on their surface (E-A/P-CeO2). The as-designed E-A/P-CeO2 features highly effective BBB crossing via receptor-mediated transcytosis to access brain tissues and synergistic elimination of ROS by both the loaded edaravone and ceria nanoparticles. As a result, the E-A/P-CeO2 with low toxicity and excellent hemo/histocompatibility can be used to effectively treat strokes due to great intracephalic uptake enhancement and, in the meantime, effectively protect the BBB, holding great potentials in stroke therapy with much mitigated harmful side effects and sequelae.