Carbon Free Radical (R∙) Inactivates NF-κB for Radical Capping Therapy.

Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon-centered free radicals (R∙) can inactivate NF-κB transcription by capping the active sites in both NF-κB and DNA. We construct a type of thermosensitive R∙ initiator loaded amphiphilic nano-micelles to facilitate intracellular delivery of R∙. At a temperature of 43°C, the generated R∙ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF-κB through radical chain reaction. As a result, both NF-κB nuclear translocation and NF-κB-DNA binding are suppressed, leading to a remarkable NF-κB inhibition of up to 94.1%. We have further applied R∙ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF-κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat-sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

Mitochondria-Targeting Type-I Photodrug: Harnessing Caspase-3 Activity for Pyroptotic Oncotherapy.

Precise control of cellular signaling events during programmed cell death is crucial yet challenging for cancer therapy. The modulation of signal transduction in cancer cells holds promise but is limited by the lack of efficient, biocompatible, and spatiotemporally controllable approaches. Here we report a photodynamic strategy that modulates both apoptotic and pyroptotic cell death by altering caspase-3 protein activity and the associated signaling crosstalk. This strategy employs a mitochondria-targeting, near-infrared activatable probe (termed M-TOP) that functions via a type-I photochemical mechanism. M-TOP is less dependent on oxygen and more effective in treating drug-resistant cancer cells, even under hypoxic conditions. Our study shows that higher doses of M-TOP induce pyroptotic cell death via the caspase-3/gasdermin-E pathway, whereas lower doses lead to apoptosis. This photodynamic method is effective across diverse gasdermin-E-expressing cancer cells. Moreover, the M-TOP mediated shift from apoptotic to pyroptotic modulation can evoke a controlled inflammatory response, leading to a robust yet balanced immune reaction. This effectively inhibits both distal tumor growth and postsurgical tumor recurrence. This work demonstrates the feasibility of modulating intracellular signaling through the rational design of photodynamic anticancer drugs.

Non-Faradaic optoelectrodes for safe electrical neuromodulation.

Nanoscale optoelectrodes hold the potential to stimulate optically individual neurons and intracellular organelles, a challenge that demands both a high-density of photoelectron storage and significant charge injection. Here, we report that zinc porphyrin, commonly used in dye-sensitized solar cells, can be self-assembled into nanorods and then coated by TiO2. The J-aggregated zinc porphyrin array enables long-range exciton diffusion and allows for fast electron transfer into TiO2. The formation of TiO2(e-) attracts positive charges around the neuron membrane, contributing to the induction of action potentials. Far-field cranial irradiation of the motor cortex using a 670 nm laser or an 850 nm femtosecond laser can modulate local neuronal firing and trigger motor responses in the hind limb of mice. The pulsed photoelectrical stimulation of neurons in the subthalamic nucleus alleviates parkinsonian symptoms in mice, improving abnormal stepping and enhancing the activity of dopaminergic neurons. Our results suggest injectable nanoscopic optoelectrodes for optical neuromodulation with high efficiency and negligible side effects.

Brazilin-Ce nanoparticles attenuate inflammation by de/anti-phosphorylation of IKKß.

Inflammation is associated with a series of diseases like cancer, cardiovascular disease and infection, and phosphorylation/dephosphorylation modification of proteins are important in inflammation regulation. Here we designed and synthesized a novel Brazilin-Ce nanoparticle (BX-Ce NPs) using Brazilin, which has been used for anti-inflammation in cardiovascular diseases but with narrow therapeutic window, and Cerium (IV), a lanthanide which has the general activity in catalyzing the hydrolysis of phosphoester bonds, to conferring de/anti-phosphorylation of IKKß. We found that BX-Ce NPs specifically bound to Asn225 and Lys428 of IKKß and inhibited its phosphorylation at Ser181, contributing to appreciably anti-inflammatory effect in cellulo (IC50 = 2.5 µM). In vivo mouse models of myocardial infarction and sepsis also showed that the BX-Ce NPs significantly ameliorated myocardial injury and improved survival in mice with experimental sepsis through downregulating phosphorylation of IKKß. These findings provided insights for developing metal nanoparticles for guided ion interfere therapy, particularly synergistically target de/anti-phosphorylation as promising therapeutic agents for inflammation and related diseases.

Successful treatment of epidermodysplasia verruciformis with a combination of 5-aminolevulinic acid photodynamic therapy and surgery.

Epidermodysplasia verruciformis (EV) is a rare inherited immune disease characterized by pityriasis versicolor-like macules, hyperpigmented or hypopigmented warty papules and irregular reddish-brown plaques, mainly on the face, neck and extremities. Some therapeutic options include medications, lifestyle changes, ALA-PDT, surgery and so on. But there is no cure for EV and thus the clinical management is challenging. We report a case of EV that was refractory to multiple therapies and achieved an encouraging result with a combination therapy of surgery and 5-aminolevulinic acid photodynamic therapy (ALA-PDT).

An atypical case of incontinentia pigmenti with a hypomorphic variant.

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects skin, hair, teeth, eyes and central nervous system. We present the case of a female patient with mild IP caused by a hypomorphic pathogenic variant of the inhibitor of the kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG) gene. This is the first report of a female IP patient with the hypomorphic variant, NM_001099856.6: c.1423dup, which is causative of anhidrotic ectodermal dysplasia with immune deficiency in males.

Ultrasound-Driven Non-Metallic Fenton-Active Center Construction for Extensive Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an emerging tumor microenvironment-responsive cancer therapeutic strategy based on Fenton/Fenton-like reactions. However, the effectiveness of CDT is subject to the slow kinetic rate and non-homogeneous distribution of H2 O2 . In this study, a conceptual non-metallic "Fenton-active" center construction strategy is proposed to enhance CDT efficiency using Bi0.44 Ba0.06 Na0.5 TiO2.97 (BNBT-6) nanocrystals. The separated charge carriers under a piezoelectric-induced electric field synchronize the oxidation of H2 O and reduction of H2 O2 , which consequently increases hydroxyl radical (·OH) yield even under low H2 O2 levels. Moreover, acceptor doping induces electron-rich oxygen vacancies to facilitate the dissociation of H2 O2 and H2 O and further promote ·OH generation. In vitro and in vivo experiments demonstrate that BNBT-6 induces extensive intracellular oxidative stress and enhances cell-killing efficiency by activating necroptosis in addition to the conventional apoptotic pathway. This study proposes a novel design approach for nanomaterials used in CDT and presents a new treatment strategy for apoptosis-resistant tumors.

Redox-active polyphenol nanoparticles deprive endogenous glutathione of electrons for ROS generation and tumor chemodynamic therapy.

Chemodynamic therapy (CDT) based on generating reactive oxygen species (ROS) is promising for cancer treatment. However, the intrinsic H2O2 is deficient for CDT, and glutathione (GSH) eliminates ROS to protect tumor cells from ROS cytotoxicity. Herein, we propose a strategy to switch the electron flow direction of GSH for O2 reduction and ROS generation rather than ROS clearance by using P(DA-Fc) nanoparticles, which are polymerized from ferrocenecarboxylic acid (Fc) coupled dopamine. P(DA-Fc) NPs with phenol-quinone conversion ability mimic NOX enzyme to deprive electrons from GSH to reduce O2 for H2O2 generation; the following •OH release can be triggered by Fc. Semiquinone radicals in P(DA-Fc) are significantly enhanced after GSH treatment, further demonstrated with strong single-electron reduction ability by calculation. In vitro and in vivo experiments indicate that P(DA-Fc) can consume intrinsic GSH to produce endogenous ROS; ROS generation strongly depends on GSH/pH level and eventually causes tumor cell death. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to ROS producer, explores new roles of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve the efficiency of CDT. STATEMENT OF SIGNIFICANCE: P(DA-Fc) nanoparticles performing tumor microenvironment response capacity and tumor reductive power utilize ability were fabricated for CDT tumor suppression. After endocytosis by tumor cells, P(DA-Fc) deprived GSH of electrons for H2O2 and •OH release, mimicking the intrinsic ROS production conducted by NADPH, further inducing tumor cell necrosis and apoptosis. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to producer, explores new functions of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve CDT efficiency.

Fusing Positive and Negative CT Contrast Nanoagent for the Sensitive Detection of Hepatoma.

Positive computed tomography (CT) contrast nanoagent has significant applications in diagnosing tumors. However, the sensitive differentiation between hepatoma and normal liver tissue remains challenging. This challenge arises primarily because both normal liver and hepatoma tissues capture the nanoagent, resulting in similar positive CT contrasts. Here, a strategy for fusing positive and negative CT contrast nanoagent is proposed to detect hepatoma. A nanoagent Hf-MOF@AB@PVP initially generates a positive CT contrast signal of 120.3 HU in the liver. Subsequently, it can specifically respond to the acidic microenvironment of hepatoma to generate H2 , further achieving a negative contrast of -96.0 HU. More importantly, the relative position between the negative and positive signals area is helpful to determine the location of hepatoma and normal liver tissues. The distinct contrast difference of 216.3 HU and relative orientation between normal liver and tumor tissues are meaningful to sensitively distinguish hepatoma from normal liver tissue utilizing CT imaging.

Treatment of nasal squamous cell carcinoma with combination of surgery and photodynamic therapy.

Cutaneous squamous cell carcinoma (cSCC) is a common malignant skin tumor. Some invasive cSCC can cause severe cosmetic damage; therefore, comprehensive measures should be taken. Here, we present a case of a 48-year-old male patient with invasive cSCC on the nose. The lesion recurred twice after excision in the other hospital. After admission, the patient underwent surgical excision; however, the tumor remained because of its deep infiltration, and we left the wound exposed without repair. During the period of open-wound, the patient received 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) to completely clear the residual tumors, and multipoint biopsies were performed to monitor the tumor remission process. We reconstructed the defect by using bilateral flaps after complete remission. The tumor did not recur in 63 months of follow-up after reconstruction. Open-wound treatment should be considered for tumors that occur at high-risk sites such as the nose. Surgery combined with PDT may be an efficient method for treating cSCC.

SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.

Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-ßTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.

Tissue RNA Sequencing Reveals Novel Biomarkers Associated with Postoperative Keloid Recurrence.

Keloids can be resected through surgery, but they may still recur. The purpose of this study was to explore the biomarkers to predict the postoperative recurrence of keloids. Patients who underwent surgical treatment and postoperative superficial X-ray radiation between January 2019 and December 2020 were recruited with clinical data and keloid samples for RNA-seq. By screening differentially expressed genes (DEGs) between postoperative recurrent and non-recurrent sample groups and constructing a co-expression network via the weighted gene co-expression network analysis (WGCNA), an immunity-related module was chosen for subsequent analysis. By constructing a DEG co-expression network and using the Molecular Complex Detection (MCODE) algorithm, five hub genes were identified in the key module. Receiver Operating Characteristic (ROC) curve analysis showed that the area under the curve (AUC) for the five combined hub genes was 0.776. The result of qRT-PCR showed that CHI3L1, IL1RN, MMP7, TNFAIP3, and TNFAIP6 were upregulated in the recurrent group with statistical significance (p < 0.05). Immune infiltration analysis showed that mast cells, macrophages, and T cells were the major components of the keloid immune microenvironment. This study provides potential biomarkers for predicting keloid recurrence and offers insights into genetic targets for recurrence prevention.

MnS Nanocapsule Mediates Mitochondrial Membrane Permeability Transition for Tumor Ion-Interference Therapy.

"Structure subserves function" is one fundamental biological maxim, and so the biological membrane that delimits the regions primarily serves as the margin between life and death for individual cells. Here, an Oswald ripening mechanism-guided solvothermal method was proposed for the synthesis of uniform MnS nanocapsules assembled with metastable γ-MnS nanocrystals. Through designing the physicochemical properties, MnS nanocapsules would disaggregate into small γ-MnS nanocrystals in a tumor acidic environment, with the surface potential switched from negative to positive, thus showing conspicuous delivery performance. More significantly, the specific accumulation of Mn2+ in mitochondria was promoted due to the downregulation of mitochondrial calcium uptake 1 (MICU1) by the formed H2S, thus leading to serious mitochondrial Mn-poisoning for membrane permeability increase and then tumor apoptosis. This study provides a synthesis strategy of metal sulfide nanocapsules and encourages multidisciplinary researchers to focus on ion-cancer crosstalk for the development of an antitumor strategy.

Treatment of severe hidradenitis suppurativa with a combination of 5-aminolevulinic acid photodynamic therapy, surgery, and secukinumab.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by nodules, abscesses, fistulas, sinus tracts, and scars, typically in intertriginous areas (Sabat et al., 2022). Therapeutic options include medications, surgical interventions, and physiotherapy; however, clinical management is challenging. We report a case of HS that was refractory to multiple treatments and achieved complete remission with a combination therapy of surgery, 5-aminolevulinic acid photodynamic therapy (ALA-PDT), and secukinumab.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Photodynamic therapy combined with surgery versus Mohs micrographic surgery for the treatment of difficult-to-treat basal cell carcinoma: a retrospective clinical study.

BACKGROUND: Mohs micrographic surgery (MMS) is the preferable surgery for difficult -to-treat basal cell carcinoma (BCC) but is an expensive, labor-intensive, and time-consuming technique. The aim of this study is to compare the efficacy and safety of photodynamic therapy combined with surgery(S-PDT) versus Mohs micrographic surgery (MMS) for the treatment of difficult-to-treat BCC. METHODS: This was a retrospective, comparative study. A total of 32 patients, 16 patients with 48 lesions, were treated with S-PDT, and the other 16 patients with 17 lesions treated by MMS were enrolled in this study. Follow-up was at least 36 months posttreatment. RESULTS: The recurrence rate was no statistical difference between the S-PDT and MMS (p = 1.000, Fishers exact test). The median follow-up was 42.5 months (range 36-63 months). The mean healing time in the S-PDT [17.9 d (SD 9.8)] is longer than in MMS [7.5 d (SD 1.5)] during follow-up (p＜.001, Independent T-test). On the whole, the cosmetic outcome of patients in S-PDT was statistically no significant difference with that in MMS according to a 4-point scale (p = .719, chi-squared test). CONCLUSIONS: S-PDT is a safe, effective, and novel cosmetic treatment, which holds the potential to be an alternative treatment to MMS for some cases.

Immune-related risk score: An immune-cell-pair-based prognostic model for cutaneous melanoma.

Background: Melanoma is among the most malignant immunologic tumor types and is associated with high mortality. However, a considerable number of melanoma patients cannot benefit from immunotherapy owing to individual differences. This study attempts to build a novel prediction model of melanoma that fully considers individual differences in the tumor microenvironment. Methods: An immune-related risk score (IRRS) was constructed based on cutaneous melanoma data from The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was used to calculate immune enrichment scores of 28 immune cell signatures. We performed pairwise comparisons to obtain scores for cell pairs based on the difference in the abundance of immune cells within each sample. The resulting cell pair scores, in the form of a matrix of relative values of immune cells, formed the core of the IRRS. Results: The area under the curve (AUC) for the IRRS was over 0.700, and when the IRRS was combined with clinical information, the AUC reached 0.785, 0.817, and 0.801 for the 1-, 3-, and 5-year survival, respectively. Differentially expressed genes between the two groups were enriched in staphylococcal infection and estrogen metabolism pathway. The low IRRS group showed a better immunotherapeutic response and exhibited more neoantigens, richer T-cell receptor and B-cell receptor diversity, and higher tumor mutation burden. Conclusion: The IRRS enables a good prediction of prognosis and immunotherapy effect, based on the difference in the relative abundance of different types of infiltrating immune cells, and could provide support for further research in melanoma.

Heterostructures with Built-in Electric Fields for Long-lasting Chemodynamic Therapy.

Sustained signal activation by hydroxyl radicals (⋅OH) has great significance, especially for tumor treatment, but remains challenging. Here, a built-in electric field (BIEF)-driven strategy was proposed for sustainable generation of ⋅OH, thereby achieving long-lasting chemodynamic therapy (LCDT). As a proof of concept, a novel Janus-like Fe@Fe3 O4 -Cu2 O heterogeneous catalyst was designed and synthesized, in which the BIEF induced the transfer of electrons in the Fe core to the surface, reducing ≡Cu2+ to ≡Cu+ , thus achieving continuous Fenton-like reactions and ⋅OH release for over 18 h, which is approximately 12 times longer than that of Fe3 O4 -Cu2 O and 72 times longer than that of Cu2 O nanoparticles. In vitro and in vivo antitumor results indicated that sustained ⋅OH levels led to persistent extracellular regulated protein kinases (ERK) signal activation and irreparable oxidative damage to tumor cells, which promoted irreversible tumor apoptosis. Importantly, this strategy provides ideas for developing long-acting nanoplatforms for various applications.

Long Non-Coding RNA uc003jox.1 Promotes Keloid Fibroblast Proliferation and Invasion Through Activating the PI3K/AKT Signaling Pathway.

The pathogenesis of keloids is complex and unclear, and the treatment of this condition remains challenging. The long non-coding RNA uc003jox.1 is highly expressed in keloid tissues compared with in normal skin tissues. We assessed the role of uc003jox.1 in keloid fibroblasts and its underlying mechanism, focusing on the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Keloid fibroblasts were transfected with a small interfering RNA targeting uc003jox.1. Colony formation, transwell, and flow cytometry assays were conducted to evaluate the proliferation, invasion, and apoptosis of keloid fibroblasts, respectively. The interaction between uc003jox.1 and the PI3K/AKT pathway was explored by using polymerase chain reaction and western blotting. Knockdown of uc003jox.1 markedly suppressed keloid fibroblast proliferation, clone-forming activity, and invasion, as well as promoted apoptosis. Silencing of uc003jox.1 decreased the phosphorylation levels of PI3K, AKT, and mammalian target of rapamycin and increased both the mRNA and protein expression levels of phosphatase and tensin homolog. Our in vitro results suggest that the long non-coding RNA uc003jox.1 can be used as a biomarker for keloid fibroblasts and that its expression is closely related to the proliferation and invasion of keloid fibroblasts through the PI3K/AKT/mammalian target of rapamycin pathway. Thus, uc003jox.1 shows potential as a treatment target for keloids.

Blocking Spatiotemporal Crosstalk between Subcellular Organelles for Enhancing Anticancer Therapy with Nanointercepters.

The spatiotemporal characterization of signaling crosstalk between subcellular organelles is crucial for the therapeutic effect of malignant tumors. Blocking interactive crosstalk in this fashion is significant but challenging. Herein, a communication interception strategy is reported, which blocks spatiotemporal crosstalk between subcellular organelles for cancer therapy with underlying molecular mechanisms. Briefly, amorphous-core@crystalline-shell Fe@Fe3 O4 nanoparticles (ACFeNPs) are fabricated to specifically block the crosstalk between lysosomes and endoplasmic reticulum (ER) by hydroxyl radicals generated along with their trajectory through heterogeneous Fenton reaction. ACFeNPs initially enter lysosomes and trigger autophagy, then continuous lysosomal damage blocks the generation of functional autolysosomes, which mediates ER-lysosome crosstalk, thus the autophagy is paralyzed. Thereafter, released ACFeNPs from lysosomes induce ER stress. Without the alleviation by autophagy, the ER-stress-associated apoptotic pathway is fully activated, resulting in a remarkable therapeutic effect. This strategy provides a wide venue for nanomedicine to exert biological advantages and confers new perspective for the design of novel anticancer drugs.