The advancement of cell-based drug delivery systems (Cell-DDS) enables precise tumor targeting. Utilizing bone marrow mesenchymal stem cells (BMSC) as carriers, transferrin (Tf)-modified BMSC (BMSCTf) were engineered via sugar metabolism replacement and click chemistry. Liposomes co-encapsulating phthalocyanine (Pc) and oxygen-carrying perfluorohexane (PFH) were integrated with BMSCTf through membrane fusion, constructing the Tf-functionalized delivery system Pc/O₂@BMSCTf. This system achieved Pc loading efficiency of 1.7 μg per 10⁵ cells and an oxygen-carrying capacity of 11.2 μg per 10⁷ cells, demonstrating active tumor targeting, significant antitumor efficacy in vitro and in vivo, and high biocompatibility. At tumor sites, localized near-infrared irradiation triggered Pc-mediated ROS generation, while the nanoliposomes provided real-time oxygen replenishment, overcoming hypoxia to potentiate photodynamic therapy (PDT). This novel stem cell-based drug delivery system represents a promising strategy for targeted tumor therapy.

OBJECTIVES:Thyroid cancer (TC) is the most common endocrine malignancy, and bone metastasis (BM) is the second most common type of metastasis after lung. BM is associated with a poor prognosis; however, relevant research remains limited. This study aims to evaluate the prognostic factors and survival outcomes in patients with thyroid cancer with bone metastasis (TCBM). METHODS:Data from patients with TCBM were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox proportional hazards regression models were used to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. RESULTS:A total of 696 TCBM patients from 2010 to 2021 were included. Among these, patients aged ≥55 years (P < .001); those with anaplastic TC (P < .001); those with brain, liver, and lung metastases (all P < .05); and those with T4 stage disease (P = .011) significantly reduced overall survival. Significant factors for cancer-specific survival included anaplastic TC (P < .001), liver (P = .010) and lung metastases (P < .001), and radioisotope treatment (P < .001). CONCLUSION:This study highlights the critical role of age, pathological subtype, metastatic lesions, and radioisotope therapy in determining the prognosis of TCBM. These findings contribute to providing more rational treatment decisions and risk stratification for patients with TCBM.

With the advancements in nanotechnology and biomaterials science, the development of nanodrug delivery systems (Nano-DDSs) has provided opportunities for the realization of precise targeted treatment of malignant tumors. Liposomes have become a type of DDS with early clinical application and mature development due to their excellent tissue-targeting capacity and outstanding biocompatibility. However, several obstacles remain, such as recognition and clearance by the immune system, a short half-life, and poor tumor targeting. To address these problems, we propose a new method to transform liposomes, using fusion to reassemble the extracted natural cell membranes and artificial phospholipids to form a composite nanolipid carrier (recombined lipid nanocarriers (RLNs)). We evaluated the different types of cell membrane composite lipid nanocarriers based on parameters such as particle size, stability, drug loading and release capabilities, in vitro and in vivo tumor-targeting efficacy, and safety. The results indicated that these novel tumor cell-derived membrane fusion lipid nanocarriers exhibited promising antitumor effects and safety profiles, offering insights for precision cancer treatment. Schematic illustration of the cell membrane fusion composite lipid nanocarrier RLNs and its antitumor effects. Tumor cell-derived membrane fusion lipid nanocarriers (HeLa-RLNs) exhibit promising antitumor effects and safety profiles.

Next-generation sequencing (NGS) is of great benefit to clinical practice in terms of identifying genetic alterations. This study aims to clarify the gene background and its influence on thyroid tumors in the Chinese population. NGS data and corresponding clinicopathological features (sex, age, tumor size, extrathyroidal invasion, metastasis, multifocality, and TNM stage) were collected and analyzed retrospectively from 2844 individual thyroid tumor samples from July 2021 to August 2022. Among the cohort, 2337 (82%) cases possess genetic alterations, including BRAF (71%), RAS (4%), RET/PTC (4%), TERT (3%), RET (2.2%), and TP53 (1.4%). Diagnostic sensitivity before surgery can be significantly increased from 0.76 to 0.91 when cytology is supplemented by NGS. Our results show that BRAF-positive papillary thyroid cancer (PTC) patients tend to have older age, smaller tumor size, less vascular invasion, more frequent tumor multifocality, and a significantly higher cervical lymph node metastatic rate. Mutation at RET gene codons 918 and 634 is strongly correlated with medullary thyroid cancer. However, it did not display more invasive clinical characteristics. TERT-positive patients are more likely to have older age, and have larger tumor size, more tumor invasiveness, and more advanced TNM stage, indicating a poor prognosis. Patients with TERT, RET/PTC1, and CHEK2 mutations are more susceptible to lateral lymph node metastasis. In conclusion, NGS can be a useful tool that provides practical gene evidence in the process of diagnosis and treatment in thyroid tumors.

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late -stage PTC. Here, we used single -cell RNA sequencing (scRNA-Seq) to generate a single -cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13 + T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Last, murine experiments and scRNA-Seq analysis of a treated patient's tumor demonstrated that famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. We displayed the cellular landscape of ATC and PTC, finding that CXCL13 + T cells and early TLS might make ATC more sensitive to immunotherapy.

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.

This paper presents the design of a new type of intelligent and versatile all-in-one therapeutic nanoplatform for the co-delivery of chemotherapeutic drugs and photosensitizers to facilitate multimodal antitumor treatment; the system is based on hyaluronic acid (HA)-modified manganese dioxide (MnO2)-enveloped hollow porous copper sulfide (CuS) nanoparticles (CuS@MnO2/HA NPs). In this system, a CuS inner shell allows for the co-loading of doxorubicin (DOX) and indocyanine green (ICG) and induces photothermal effects, and a biodegradable MnO2 external shell affords on-demand tumor microenvironment (TME)-triggered release and catalase- andFenton-like activities. Moreover, the HA modification endows the system with a CD44 receptor-mediated tumor-targeting property. The formulated DOX and ICG co-loaded CuS@MnO2/HA (DOX/ICG-CuS@MnO2/HA) NPs were found to exhibit excellent photothermal performance both in vitro and in vivo. In addition, DOX/ICG-CuS@MnO2/HA NPs were found to display both TME and near-infrared (NIR)-responsive controlled release properties. The NPs also have a superior reactive oxygen species (ROS) generation capacity due to the combination of enhanced ICG-induced singlet oxygen and CuS@MnO2-mediated hydroxyl radicals. The cellular uptake, fluorescence imaging property, cytotoxicity, and thermal imaging of these NPs were also evaluated. In tumor-bearing mice, the DOX/ICG-CuS@MnO2/HA NPs displayeda superior antitumor efficacy (2.57-fold) as compared with free DOX. Therefore, the developed DOX/ICG-CuS@MnO2/HA NPs have a great potential for use as an all-in-one nanotherapeutic agent for the efficient and precise induction of chemo/photothermal/photodynamic/chemodynamic therapy with superior antitumor efficacy and fewer side effects.

Tumour microenvironment (TME)-targeting nanoparticles (NPs) were developed based on Methanococcus jannaschii small heat shock proteins (Mj-sHSPs). Transactivator of transcription (TAT) were modified on the surface of Mj-sHSPs (T-HSPs) to enhance their cellular internalization ability (CIA), and a pH/enzyme dual sensitive PEG/N-(2-aminoethyl)piperidine-hyaluronic acid (PAHA) coat was combined with T-HSPs (PT-HSPs). PT-HSP NPs exhibited multi-layered morphologies and good stability against plasma protein adsorption. The release of paclitaxel (PTX) from PT-HSP NPs was negligible at physiological pH. Under conditions similar to the TME (acidic pH and overexpressed hyaluronidase (HAase)), the PAHA coat deshielded from PT-HSP NPs because of two factors: charge reversal and HAase degradation. Once the PAHA coat was shed, the size of the NPs decreased; its surface charge became positive; and remarkable drug release was triggered. Cellular experiments indicated that the CIA of PT-HSPs was shielded in the microenvironment of normal cells and recovered in that of tumour cells. In vivo imaging exhibited that the PT-HSP NPs had an impressive tumour targeting ability compared with the uncoated controls. The antitumor efficacy in vivo demonstrated that tumour-bearing mice treated with PTX-loaded PT-HSP NPs achieved better anti-tumour effects and safety than the Taxol formulation. In summary, this study provided Mj-sHSP NPs with coats that could be shed in response to the particular pH and enzymes in the TME, which improved the efficacy of tumour therapy. STATEMENT OF SIGNIFICANCE: This study reports on tumor microenvironment-targeting protein-based nanoparticles (PT-HSP NPs) for targeted tumor therapy. The NPs had a multilayered structure: a protein cage, a TAT cationic layer, and a dual-sensitive coat. PT-HSP NPs exhibited multilayered morphology, with good stability against plasma protein adsorption, and PTX release negligible at physiological pH. Under the tumor microenvironment (acidic pH and overexpressed HAase), PAHA coat deshielded from PT-HSP NPs due to two factors: the charge reversal induced by protonation of piperidines in PAHA and HAase degradation. The results of cellular uptake, cytotoxicity, in vivo imaging, and tumor inhibition experiments confirmed that PT-HSP NPs exhibited promising tumor targeting efficacy in vitro and in vivo.