Nano-CaO2, with its multifunctional properties, has emerged as a promising candidate for tumor therapy. Its ability to release Ca2+ and H2O2 into the tumor microenvironment has positively modulated abnormal calcium signaling and kinetic therapy. Moreover, the indirectly produced O22− by CaO2 can alleviate hypoxic conditions. On the one hand, the accumulation of Ca2+ can lead to various tumor cell apoptosis events, such as calcium overload and tumor calcification. On the other hand, the released H2O2 can convert into more toxic reactive oxygen species (ROS) via exogenous stimulation and endogenous regulation, thereby making nano-CaO2 a versatile tool in modern medicine, exhibiting its invaluable and irreplaceable medical value in tumor therapy. Hence, a comprehensive review of the recent advances in the nano-CaO2 platform is imperative. This review provides an overview of the conventional synthesis strategies for nano-CaO2. It elucidates the potential role of the nano-CaO2 nanoplatforms in various tumor treatment strategies, including monotherapy and combination therapy, in detail. Given the remarkable outcomes achieved to date and the challenges that of future clinical translation, this work predicts the future research directions. This review will encourage further development of the metal oxide nanomedicine family, epitomized by nano-CaO2.

Transmural skip lesions are pathognomonic for Crohn's disease (CD). Despite advances toward CD treatment, disease recurrence remains a problem. CD requires novel therapies to modulate localized intestinal inflammation and promote intestinal epithelium healing. Human neonatal cardiac-derived mesenchymal stem cells (nMSCs) demonstrate immune cell modulation accompanied by improved cardiac function recovery in myocardial infarction models. In the established CD-like ileitis SAMP mouse model, direct skip lesion injection of nMSCs prevents ileal skip lesion growth and significantly down-regulates the pro-inflammatory milieu. Significant reduction in the percentage of skip lesion CD68+ macrophages (M1 Mφ, pro-inflammatory) accompanied by an increase of CD206+ macrophages (M2 Mφ, anti-inflammatory/pro-regenerative) is observed in skip lesions following nMSCs injection compared to non-injected and placebo controls (p < 0.05). Skip lesion size is significantly reduced along with pro-inflammatory cytokines IFN-y and TNF-α, with an increase in intestinal tissue anti-inflammatory cytokine IL-10 production. nMSCs are also retained within skip lesions 5 weeks post-treatment. nMSC administration promotes wound remodeling by modulating inflammatory immune cells and by increasing small bowel gastrointestinal transit with concomitant decreased segment gross pathology score compared to placebo control. Data from this study demonstrate that direct injection of nMSCs into ileal skip lesions attenuates inflammation and improves intestinal physiology.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever, and inflammation; additionally, antitumor properties are reported. NSAIDs reduce the synthesis of prostaglandins by inhibiting the cyclooxygenase (COX) isoforms COX-1 and COX-2. As nonselective inhibition is associated with off-target effects, strategies to achieve selectivity for the clinically preferred isoform COX-2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics is reported to alter the selectivity profile through size exclusion. Inspired by these findings, isonimesulide and its carborane derivatives are prepared. The biological screening shows that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from nonactive to COX-active compounds.

Tolerogenic dendritic cells (tDCs) induces regulatory T cell (Treg) differentiation and promotes immune tolerance. However, the effective generation of tDCs in vivo to treat autoimmune diseases remains a significant challenge. In this study, the potential of 1α, 25-Dihydroxyvitamin D3 (VD3) is explored, which has been shown to promote tDCs differentiation in vitro, to induce tDCs in a mouse model of experimental autoimmune encephalomyelitis (EAE). To overcome the poor solubility of VD3 and induce autoantigen-specific Tregs, a PLGA-PEG-based nano-drug delivery system is prepared to co-deliver VD3 and myelin-oligodendrocyte glycoprotein (MOG) peptides. It is found that intradermal (i.d.) injection of NP/VD3/MOG significantly enhanced the level of antigen-specific Tregs in vivo. Furthermore, NP/VD3/MOG remarkedly delayed the onset, reduced the severity, and promoted the recovery of EAE mice. This study provides an effective strategy for the treatment of autoimmune diseases.

Allergic rhinitis, as the most common type of rhinitis, has become a global health problem. At present, oral/intranasal administration of H1-antihistamines and corticosteroids is considered to be the main therapeutic method for allergic rhinitis. However, the local bioavailability of the drug is low due to the systemic effect of drugs and nasal mucociliary clearance. More recently, a hydrogel-based intranasal delivery system (HIDS) is proposed and gradually developed as an emerging strategy for allergic rhinitis treatment by extending the residence time of drugs in a controlled manner. This review aims to highlight the advances in HIDS for allergic rhinitis treatment. The designs and therapeutic effect of the existing HIDS in the nasal microenvironment are described in detail. This review also provides a perspective on the future opportunities and developments of HIDS. Despite its nascent status, the future clinical and translational applications of HIDS can have a transformative impact on improving the treatment of chronic inflammation in the nasal cavity.

Recently, photothermal therapy (PTT) has attracted enormous attention because of its low invasiveness, high spatiotemporal selectivity, and good therapeutic effect. Different types of photothermal conversion agents have been developed, particularly the second near-infrared window (NIR-II, 1000–1700 nm) organic small molecular dyes which have become an attractive research direction. Herein, a novel and simple donor–acceptor–donor (D–A–D) type NIR-II dye SeC is designed and synthesized with 2λ4δ2-[1,2,5]selenadiazolo[3,4-f]-2,1,3-benzothiadiazole structure. To improve capability of SeC for biomedical applications, SeC molecules are encapsulated into DSPE-PEG2000 to construct nanoparticles SeC-NPs, which show high photostability and biocompatibility. More importantly, SeC-NPs exhibited an excellent photothermal performance and display high photothermal conversion efficiency (PCE) of 62% under 808 nm excitation. Because of favorable fluorescence property in NIR-II window and high PCE, SeC-NPs are successfully used for NIR-II imaging and PTT of 4T1 tumor-bearing mice models. In vivo studies demonstrate SeC-NPs’ ability to suppress tumor growth under NIR photoirradiation without visible damage to main organs. Overall, this study develops a strategy to design a simple small molecule dye containing selenium for NIR-II imaging, and SeC-NPs shows high performance for PTT toward tumor.

The combination therapy of targeted drugs and immune checkpoint inhibitors has shown prominent success. In addition to blocking mutated oncogene downstream signaling, the immunological mechanism(s) underlying the anti-tumor effect of targeted-immuno-therapy is not clear. In this study, anlotinib, a novel pan-targeted tyrosine kinase receptor inhibitor (pTKI), is combined with anti-PD1 (αPD1) as a therapeutic regimen applying to an immunocompetent mouse tumor model. Anlotinib induces immunogenic cell death (ICD), elicits anti-tumor inflammation and infiltration, and activation of DCs and CD8+ T cells, which are enhanced by αPD1. Furthermore, anlotinib reduces KC/MCP-1 secretion by attenuating educational effect that cancer cells imposed on tumor-associated macrophages (TAMs) and prevents their M2 polarization by inhibiting AKT/mTORC1 and Pparδ pathways. Importantly, anlotinib plus αPD1 prolongs median progression-free survival time compared with standard chemotherapy plus pembrolizumab as the 1st line treatment in non-small cell lung cancer (NSCLC) patients. Thus, anlotinib treatment elicits both innate and adaptive anti-tumor immune responses while αPD1 enhances its potency. This study provides strong evidence that combination of targeted therapy and immunotherapy is a promising regimen for treating NSCLC.

Otitis media (OM) is a common bacterial disease in otolaryngology, which has a high incidence rate and seriously affects people's health and quality of life. The abuse of antibiotics is a severe public health problem worldwide, contributing to the emergence of multidrug-resistant bacteria and vestibular/cochlear damage, leading to sensorineural hearing loss. In this study, PLGA-PEG-PLGA thermosensitive hydrogel (PPPTH) is employed as a drug delivery carrier to deliver metastable cystine-denoted iron sulfides compounds (Cys-nFeS) to treat Staphylococcus aureus (S. aureus)-induced OM by topical injection through the eardrum. The combination of Cys-nFeS and PPPTH (Cys-nFeS/PPPTH) prevents Cys-nFeS from rapidly oxidizing and constantly releasing Cys-nFeS, fulfilling the goal of continuous therapy. The destructive effect of Cys-nFeS/PPPTH on bacteria and bacterial biofilms in vitro and in vivo is evaluated. The results show that Cys-nFeS/PPPTH has good antibacterial and biofilm destruction effects, low cytotoxicity, and excellent anti-inflammatory effects. Moreover, it is found that Cys-nFeS/PPPTH can repair S. aureus-induced hearing loss in OM. This study demonstrates the promising potential of Cys-nFeS/PPPTH for middle ear delivery and antibacterial treatment.

Oesophageal squamous carcinoma (ESCC) is one of the most lethal human malignancies worldwide, especially in China, due to its late-stage diagnosis, chemoradiotherapy resistance, and lack of appropriate therapeutic targets and corresponding therapeutic formulations. In article number 2200251, Bing Jiang and co-workers review the latest genomics, diagnostics, etiology, and therapeutic researches of ESCC to provide a comprehensive discussion and seek breakthrough on the theranostics of ESCC.

Protein-based drug delivery systems have gained popularity due to their biocompatibility, straightforward surface modification, and potential for intrinsic therapeutic activity. Among therapeutic proteins, enzymes are particularly attractive because of their specificity, efficient reaction rates, regeneration after substrate turnover, and proven track record in the treatment of diseases ranging from cancer to inherited metabolic and lysosomal storage disorders. Herein, previous work on electrohydrodynamic jetting is expanded upon by developing a novel class of protein nanoparticles that features therapeutic enzymes. In particular, nanoparticles incorporating the antioxidant enzyme, catalase, at weight fractions as high as 50% are reported. Catalase-based synthetic protein nanoparticles (CAT-SPNPs) demonstrate sustained antioxidative activity, retain significantly enhanced enzymatic activity compared to its solute form, and overall demonstrate good structural stability. Moreover, surface functionalization of CAT-SPNPs with targeting antibodies results in ≈12.5-fold increase in uptake over unmodified control particles. Importantly, CAT-SPNPs exert protection from oxidative stress, as indicated by significant increase in viability and reduction in LDH release compared to equivalent amounts of free catalase. Taken together, the work establishes targeted enzyme-based SPNPs as a platform for enhancing the drug-like properties of therapeutic enzymes.

Adapted oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle activations are essential tumor microenvironments for abnormal energy consumption to acquire malignancy and drug resistance during cancer development and progression. To elucidate the molecular mechanism related to the mitochondrial metabolic dynamics and drug resistance in glioblastoma (GBM), a longitudinal GBM orthotopic mouse model with acquired resistance to bevacizumab is established. The longitudinal proteomic analysis results show that OXPHOS, TCA, and calcium signaling gene sets are enriched in the bevacizumab pre-resistance phase for preparing resistance phase. Then, the APEX system to GBM to biotinylate and purify proteins of the mitochondria matrix is applied. The organelle specific proteomic analysis shows that the pore-forming subunits of the mitochondrial calcium uniporter protein (MCU) are essential for acquiring bevacizumab resistance. Additionally, a combination effect of hypoxia and the MCU-specific inhibitor DS16570511 in vitro shows that cell growth and proliferation are reduced via inhibition of NF-κB and CEBP/β signaling pathways. In conclusion, the hypoxic tumor microenvironment induced by bevacizumab treatment affects mitochondrial metabolic dynamics, and targeting MCU is a promising therapeutic option in combination with bevacizumab in recurrent GBM.

The solid tumor microenvironment presents many challenges for immunotherapy that must be addressed for clinical relevance. This review will highlight research that has attempted to tackle these challenges and summarize recent therapeutic approaches to enhance both native and engineered T cell functions through hydrogel delivery. Different types of hydrogels are presented in this paper and organized based on purpose of the research: activation and expansion, delivery methods, co-delivery of immunostimulating agents, and overcoming tumor microenvironment barriers. Perspectives in the future of solid cancer immunotherapy are also discussed to share opinion on necessary research for the success in this field.

This study is designed to explore the roles of the T-Box transcription factor 2 (TBX2)-Wnt family member 3A (WNT3A) axis in colorectal cancer. Clinical specimens are collected from the colorectal cancer patients and the volunteers. TBX2 overexpression and knockout stable cell lines and WNT3A knockdown cells are constructed. The xenograft animal model is established by using those stable cell lines. Cell proliferation, migration, and invasion are evaluated. Quantitative reverse transcription polymerase chain reaction and Western blotting are used to determine the expression levels of target biomarkers. ChIP analysis is utilized to assess the enrichment of TBX2 on the promoter site of WNT3A. An elevation of TBX2 is observed in colorectal cancer specimens and TBX2 expression is positively correlated to cell proliferation, migration, and invasion. Besides, TBX2 regulates the expressions of biomarkers relevant to epithelial-mesenchymal transition (EMT) and WNT3A signaling pathways. Interestingly, WNT3A also promotes the HCT116 cell proliferation, migration, invasion by the regulation of EMT-related biomarkers. The in vivo study shows that the TBX2-WNT3A axis promotes tumor growth. TBX2-WNT3A axis promotes the development of colorectal cancer.

Radiation skin injury (RSI) is a frequent adverse effect of radiation therapy for malignant tumors. It often leads to problems such as decreased quality of life in patients and interferes with the normal course of radiation therapy (RT). With the rising incidence of tumors and the burgeoning number of patients undergoing RT, the care of RSI is of crucial importance in cancer patient treatment. Currently, drugs and biomaterials are widely used in the care of RSI. However, there is no international consensus on the current protocol for the therapeutic care of RSI. Many drugs and biomaterials cannot be applied to the appropriate type of radiation dermatitis, resulting in unfavorable results in the therapeutic care of RSI. The choice of appropriate drugs and biomaterials for the therapeutic care of the different types of RSI is essential to improving the quality of life of patients. This article first reviews the main mechanisms of acute and chronic RSI. Subsequently, the application of drugs and novel biomaterials in the preventive, acute, and chronic phases of the care of RSI is summarized. Finally, the suggestions and protocols for the application of novel biomaterials in the care of RSI are discussed, as are the current challenges and future prospects for the development of combined biomaterials and integrated care solutions.

A promising approach enhancing osteosarcoma (OS) prognosis involves the combination of various techniques, such as chemo- and photodynamic therapy, delivered through nanocarriers for synergistic cell death. Among the potential candidates for improving drug accumulation at the tumor site, mesenchymal stromal cells (MSCs) exhibit a significant advantage due to their tumor-homing ability and intracellular drug retention. This study evaluates the efficacy of chemo-releasing and photoactive bimodal nanoparticles, kPCe6 NPs, delivered via MSCs. In vitro analyses show that cells internalize and retain kPCe6 NPs in a dose-dependent manner and that kPCe6-loaded cells induce massive tumor cell death in a tridimensional tumor model. Results from an in vivo orthotopic OS murine model show negligible tumor cell death upon peritumoral administration of two doses containing 106 loaded cells. To gain insight into this observation, this work investigates the role of cell dose in treatment efficacy. The results indicate that achieving a tumor reduction higher than 90% requires a substantial number of loaded cells, approximately 35% of the entire tumor mass, highlighting the criticality of the cell dose for the success of this therapeutic approach and its potential impact on clinical translation in OS patients, particularly when the number of tumor cells is limited.

Parkinson's disease (PD) is starting at younger ages. In order to reduce the risk of PD in young people, Rb3 is selected as an active ingredient and assembled into Rb3 nanoparticles (Rb3NPs)encapsulated microbubbles (MBs), shorted for Rb3NPs@MBs. This study uses focused ultrasound-mediated Rb3NPs@MBs to cross the blood–brain barrier and reach the brain lesions to be intervened in in order to explore the prevention of 1-methyl-4-phenyl-4-piperidinpropionate ester (MPTP)-induced PD by Rb3NPs@MBs and its related mechanisms. In the present study, Rb3NPs@MBs prevent MPTP-induced tyrosine hydroxylase (TH)-positive cell decreases, decrease TH expression, increase Park2 expression, and decrease expression of α-synaptonucleoprotein in the pars compactus nigra (SNc). It is found, in vitro study, that Rb3NPs treatment significantly reverses MPTP-induced apoptosis and death of PC12/SY5Y cells, which is commonly used mouse/ human neural cell lines. It is also found that Rb3NPs@MBs can prevent the production of reactive oxygen species (ROS) in SNc. Finally, it is found that DJ-1 expression decreases after Rb3NPs@MBs are introduced. Results suggest that the neuroprotective activity of Rb3NPs@MBs may be achieved by increasing the expression of DJ-1 and decreasing the production of ROS. Taken together, these data reveal that Rb3NPs@MBs play an important role in preventing memory deficiency in PD.

Gold nanorods and cyanine dyes are promising to be widely used in photothermal therapy due to their adjustable absorption wavelength and excellent photothermal conversion efficiency. However, it is unclear how gold nanorods differ from cyanine dyes in therapeutic effects. Nanocapsules are synthesized from hybrid silica encapsulated gold nanorods (AuNRs@YSiO2, hereafter GNR@YS). Composite nanocapsules (hereafter GNR@YS-CyN) are prepared from GNR@YS loaded with CyN to treat subcutaneous tumor. Cyanine dye (CyCl) with similar absorption to gold nanorods is also synthesized to match the existing commercial 808 nm laser. The results show that both materials have good therapeutic effect, but differ in healing scabs on skin tissue surface after tumor ablation. GNR@YS-CyN are superior to CyCl in the treatment of subcutaneous tumor. This may be the size effect of GNR@YS-CyN has permeability and retention enhancement effect at the tumor site. GNR@YS-CyN have no obvious dye diffusion phenomenon, which reduces the damage to normal tissue.

Hydrogels are a frequently utilized and modified biomaterial. Due to their unique tissue-like properties, they are used in various biomedical applications. Among the many types of hydrogels, bioadhesive hydrogels are of particular interest, as they provide long-term robust tissue adhesion that aids in therapeutic applicability, including drug delivery, mechanical stimulus, and in situ monitoring and diagnosis. Accordingly, this review highlights recent developments in bioadhesive hydrogels and their dermatological applications. To provide a broader view of bioadhesive hydrogels, studies regarding their assistance in skin diagnosis and the corresponding treatments are also summarized. This review comprehensively explains the importance and versatility of advanced and unique therapeutic bioadhesive hydrogels used in skin care and therapy.

Immunotherapeutics, such as bispecific T cell engagers (BiTEs), have shown promise in cancer therapies, however their efficacy against solid tumors is hindered by transport barriers. Local therapies are being investigated to improve solid tumor immunotherapies and minimize systemic toxicity. Because local therapies bypass the circulatory system, drug properties can be optimized to further enhance local efficacy. Herein, the use of a larger BiTE-like antibody-oligomer conjugate is investigated, modular T cell engagers (MoTEs), to extend the duration of activity within local tissue mimics. Specifically, an anti-CD3 antibody is modified with heterobifunctional ethylene oxide ((EO)4-12) linkers, which are subsequently modified with cancer targeting ligands (CTLs). The (EO)x molecular weight and CTL grafting densities are optimized to achieve targeted cytotoxicity within in vitro co-cultures against prostate-specific membrane antigen (PSMA) positive and human epidermal growth factor receptor 2 (HER2) positive cancer cells. In local tissue models comprised of embedded PSMA positive spheroids in collagen-hyaluronic acid hydrogels with T cells, it is demonstrated that MoTEs resulted in ≈2.5-fold greater cytotoxicity toward cancer spheroids than a PSMA targeting BiTE at longer 12-day timepoints. MoTEsmay therefore prove beneficial for local therapies by extending the duration of action after single-dose administration and establishing simple synthetic protocols to target various cancer antigens.

The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, is shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. It is investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM). Under control conditions, higher levels of Cy7-CCPM are found in PANC-1 tumors (16.7% ID g−1 at 48 h post i.v. injection) than in 4T1 tumors (11.0% ID g−1). In both models, free and nano-formulated TMX failed to improve CCPM delivery. These findings are congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicate that TMX treatment does not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, these results demonstrate that in PANC-1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor-targeted drug delivery.