Photodynamic therapy (PDT) is a promising tumor treatment modality that can convert oxygen into cytotoxic singlet oxygen (SO) via photosensitizer to ablate tumor growth. However, the uncontrolled cancer cell proliferation during tumor development and the oxygen consumption during PDT always result in an insufficient oxygen level in tumors, which can adversely affect the PDT efficiency in turn. We designed an oxygen-generating PDT nanocomplex by encapsulating a manganese dioxide nanoparticle (MnO NP) in an indocyanine green (ICG) modified hyaluronic acid nanoparticle (HANP) to overcome this limitation. Because of the excellent fluorescent and photoacoustic properties, the tumor accumulation of the ICG-HANP/MnO (IHM) nanocomplex was monitored by fluorescent imaging and photoacoustic imaging after intravenous administration into the SCC7 tumor-bearing mouse model. Both high fluorescent and photoacoustic signals were detected and found peak at 6 h post-injection (tumor-muscle ratio: 4.03 ± 0.36 for fluorescent imaging and 2.93 ± 0.13 for photoacoustic imaging). In addition, due to the high reactivity of MnO NP to HO, an unfavorable tumor cell metabolic, the oxygen content in the tumor is elevated 2.25 ± 0.07 times compared to that without IHM treatment as ultrasound imaging confirmed. After laser irradiation, significant tumor growth inhibition was observed in the IHM-treated group compared to the ICG-HANP-treated group, attributed to the beneficial oxygen-generating property of IHM for PDT. It is expected that the design of IHM will provide an alternative way of improving clinical PDT efficacy and will be widely applied in cancer theranostics.

SUMMARY Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington’s disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remain unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knock-in mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.

The delivery of therapeutic peptides for diabetes therapy is compromised by short half-lives of drugs with the consequent need for multiple daily injections that reduce patient compliance and increase treatment cost. In this study, we demonstrate a smart exendin-4 (Ex4) delivery device based on microneedle (MN)-array patches integrated with dual mineralized particles separately containing Ex4 and glucose oxidase (GOx). The dual mineralized particle-based system can specifically release Ex4 while immobilizing GOx as a result of the differential response to the microenvironment induced by biological stimuli. In this manner, the system enables glucose-responsive and closed-loop release to significantly improve Ex4 therapeutic performance. Moreover, integration of mineralized particles can enhance the mechanical strength of alginate-based MN by crosslinking to facilitate skin penetration, thus supporting painless and non-invasive transdermal administration. We believe this smart glucose-responsive Ex4 delivery holds great promise for type 2 diabetes therapy by providing safe, long-term, and on-demand Ex4 therapy.

Phototherapy is a light-triggered treatment for tumor ablation and growth inhibition via photodynamic therapy (PDT) and photothermal therapy (PTT). Despite extensive studies in this area, a major challenge is the lack of selective and effective phototherapy agents that can specifically accumulate in tumors to reach a therapeutic concentration. Although recent attempts have produced photosensitizers complexed with photothermal nanomaterials, the tedious preparation steps and poor tumor efficiency of therapy still hampers the broad utilization of these nanocarriers. Herein, we developed a CD44 targeted photoacoustic (PA) nanophototherapy agent by conjugating Indocyanine Green (ICG) to hyaluronic acid nanoparticles (HANPs) encapsulated with single-walled carbon nanotubes (SWCNTs), resulting in a theranostic nanocomplex of ICG-HANP/SWCNTs (IHANPT). We fully characterized its physical features as well as PA imaging and photothermal and photodynamic therapy properties in vitro and in vivo. Systemic delivery of IHANPT theranostic nanoparticles led to the accumulation of the targeted nanoparticles in tumors in a human cancer xenograft model in nude mice. PA imaging confirmed targeted delivery of the IHANPT nanoparticles into tumors (T/M ratio = 5.19 ± 0.3). The effect of phototherapy was demonstrated by low-power laser irradiation (808 nm, 0.8 W/cm2) to induce efficient photodynamic effect from ICG dye. The photothermal effect from the ICG and SWCNTs rapidly raised the tumor temperature to 55.4 ± 1.8 °C. As the result, significant tumor growth inhibition and marked induction of tumor cell death and necrosis were observed in the tumors in the tumors. There were no apparent systemic and local toxic effects found in the mice. The dynamic thermal stability of IHANPT was studied to ensure that PTT does not affect ICG-dependent PDT in phototherapy. Therefore, our results highlight imaging property and therapeutic effect of the novel IHANPT theranostic nanoparticle for CD44 targeted and PA image-guided dual PTT and PDT cancer therapy.

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe 3+ ) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/ photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.

The Huntington's disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age-and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment.Huntingtin | aging | degeneration | acinus | pancreas H untington's disease (HD) is caused by polyglutamine (polyQ) expansion in the N-terminal region of huntingtin (HTT). Despite its ubiquitous expression in the brain and body, mutant HTT causes selective neuronal degeneration as well as white matter atrophy in the brain (1-3). The neuronal degeneration is characterized by the preferential loss of neuronal cells in the striatum in the early disease stage and extensive neurodegeneration in a variety of brain regions in later disease stages. This progressive neurodegeneration is consistent with the late-onset neurological symptoms of HD, and age-dependent toxicity of mutant HTT is thus a characteristic of HD.HTT consists of 3,144 amino acids and is thought to be a scaffold protein that associates with a number of other proteins and participates in a wide range of cellular functions, including intracellular trafficking of a variety of proteins (1, 4). HTT is important during animal early development, as germ-line deletion of Htt leads to early death of mice at embryonic day 8.5 (5-7). A variety of HD animal models that express mutant HTT provide strong evidence for an age-dependent toxic gain of function of mutant HTT (8-12), and considerable efforts have been devoted to developing siRNA and antisense oligonucleotides to suppress the expression of mutant HTT in adult brains (13-15). Unfortunately, however, these approaches have also raised concerns that markedly suppressing HTT expression will lead to side effects by impairing HTT's normal function. To date, whether HTT has differential roles in early development and adulthood remains unknown. Clarifying these distinctions is vital if we are to develop a better strategy for treating HD.Using conditional Htt knockout mice to mate with transgenic CAG-CreER mice that express Cre-ER ubiquitously in the body and brain and transgenic mice expressing Cre-ER in neuronal cells, we generated inducible Htt knockout mice and found that loss of Htt in adult mouse brain does not cause ob...

Radiotherapy (RT) based on DNA damage and reactive oxygen species (ROS) generation has been clinically validated in various types of cancer. However, high dose-dependent induced toxicity to tissues, non-selectivity, and radioresistance greatly limit the application of RT. Herein, an oxygen-enriched X-ray nanoprocessor Hb@Hf-Ce6 nanoparticle is developed for improving the therapeutic effect of RT-radiodynamic therapy (RDT), enhancing modulation of hypoxia tumor microenvironment (TME) and promoting antitumor immune response in combination with programmed cell death protein 1 (PD-1) immune checkpoint blockade. All functional molecules are integrated into the nanoparticle based on metal-phenolic coordination, wherein one high-Z radiosensitizer (hafnium, Hf) coordinated with chlorin e6 (Ce6) modified polyphenols and a promising oxygen carrier (hemoglobin, Hb) is encapsulated for modulation of oxygen balance in the hypoxia TME. Specifically, under single X-ray irradiation, radioluminescence excited by Hf can activate photosensitizer Ce6 for ROS generation by RDT. Therefore, this combinatory strategy induces comprehensive antitumor immune response for cancer eradication and metastasis inhibition. This work presents a multifunctional metal-phenolic nanoplatform for efficient X-ray mediated RT-RDT in combination with immunotherapy and may provide a new therapeutic option for cancer treatment.

Nanotherapeutics have been investigated for years, but only modest survival benefits were observed clinic. This is partially attributed to the short and rapid elimination of nanodrug after intravenous administration. In this study, a long circulation single wall carbon nanotube (SWCNT) complex was successfully fabricated through a new SWCNT dispersion agent, evans blue (EB). The complex was endowed with fluorescent imaging and photodynamic therapy ability by self-assembly loading an albumin coupled fluorescent photosensitizer, Chlorin e6 (Ce6) via the high affinity between EB and albumin. The yielding multifunctional albumin/Ce6 loaded EB/carbon nanotube-based delivery system, named ACEC, is capable of providing fluorescent and photoacoustic imaging of tumors for optimizing therapeutic time window. Synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) were carried out as guided by imaging results at 24 h post-injection and achieved an efficient tumor ablation effect. Compared to PDT or PTT alone, the combined phototherapy managed to damage tumor and diminish tumor without recurrence. Overall, our study presents a SWCNT based theranostic system with great promising in dual modalities imaging guided PTT/PDT combined treatment of tumor. The applications of EB on SWCNT functionalization can be easily extended to the other nanomaterials for improving their in vivo stability and circulation time.