Self-Decomposable Mesoporous Doxorubicin@Silica Nanocomposites for Nuclear Targeted Chemo-Photodynamic Combination Therapy

Concerns associated with the nondegradability of silica (SiO₂)-based nanoplatforms have hindered their potential clinical translation as drug carriers. Hence, in this work, by embedding drug (doxorubicin (DOX) or methylene blue (MB), etc.) molecules into SiO₂ nanoparticles (NPs), self-decomposable drug-embedded SiO₂ NPs were prepared. Importantly, we found that the intermediate morphology during the decomposition depends on the type of the embedded drug molecules, (e.g., DOX results in mesoporous nanostructures; MB results in center-hollowed nanoshells). Second, different from previous studies, the intermediate mesoporous DOX-embedded SiO₂ (mDOX@SiO₂) NPs with radial mesopores were modified with nuclear localization signal peptides to achieve nuclear targeted DOX delivery upon the fragmentation of NPs. Meanwhile, MB (a widely used photosensitizer) was further uploaded into the mesopores to realize chemo-photodynamic combination therapy. At last, in vitro and in vivo antitumor efficacy and toxicity of the as-designed drug-delivery system were evaluated. The results showed that compared with the nontargeting and chemotherapy-only systems, the self-decomposable NPs with nuclear targeting capability and MB loading exhibited enhanced therapeutic efficacy, and no noticeable systemic toxicity was observed, indicating that the present system should be a promising paradigm in the design of SiO₂-based drug carriers

Quantum Dots-Based Multifunctional Nano-Prodrug Fabricated by Ingenious Self-Assembly Strategies for Tumor Theranostic

The rapid developments of quantum dots (QDs)-based nanoagents for imaging tumor and tracking drug delivery have been proven to be reliable nanodiagnostic techniques. Although abundant types of QD nanoagents have been developed for fighting against cancer, it still is a challenge to control their quality and achieve prefect repetition due to the complicated synthetic steps. The precise intermolecular self-assembly (SA) may afford a facile and low-cost strategy for this challenge. Herein, a pH and H₂O₂ dual-sensitive Sb–cyclodextrin (CD)–doxorubicin (DOX) molecule was designed to construct a QD-based theranostic prodrug (named as Sb–CD–DOX–ZAISe/ZnS) via host–guest strategy (1st SA strategy), in which QDs water-transfer and drug-uploading were integrated well. That is, the nano-prodrug (NPD) inherited highly luminescent properties from “host” QDs for bioimaging, as well as environment sensitivities from “guest” Sb–CD–DOX for drug release. Experimental results indicate that the Sb–CD–DOX–ZAISe/ZnS exhibited effectively passive tumor-targeting and could provide clear imaging for malignant tumors in metaphase or advanced stages; meanwhile, after coating with folic acid (FA) through electric attraction (2nd SA strategy), the final Sb–CD–DOX–ZAISe/ZnS@FA NPD showed expected pH-controlled negative-to-positive charge reversal ability and a better curative effect compared with free DOX. Hence, fabricating nanocomposites by highly efficient self-assembly strategies is favorable toward inorganic nanoparticles-based prodrug delivery system for tumor-targeting theranostic

DataSheet_1_Simultaneous editing of TCR, HLA-I/II and HLA-E resulted in enhanced universal CAR-T resistance to allo-rejection.pdf

IntroductionThe major challenge for universal chimeric antigen receptor T cell (UCAR-T) therapy is the inability to persist for a long time in patients leading to inferior efficacy clinically. The objective of this study was to design a novel UCAR-T cell that could avoid the occurrence of allo-rejection and provide effective resistance to allogeneic Natural Killer (NK) cell rejection, together with the validation of its safety and efficacy ex vivo and in vivo.MethodsWe prepared T-cell receptor (TCR), Human leukocyte antigen (HLA)-I/II triple-edited (TUCAR-T) cells and evaluated the anti-tumor efficacy ex vivo and in vivo. We measured the resistance of exogenous HLA-E expressing TUCAR-T (ETUCAR-T) to NK rejection by using an enhanced NK. Furthermore, we established the safety and efficacy of this regimen by treating Nalm6 tumor-bearing mice with a repeated high-dose infusion of ETUCAR-T. Moreover, we analyzed the effects of individual gene deficiency CAR-T on treated mice and the changes in the transcriptional profiles of different gene-edited T cells via RNA-Seq.ResultsData showed that HLA-II editing didn’t impair the anti-tumor efficacy of TUCAR-T ex vivo and in vivo and we found for the first time that HLA-II deficiency could facilitate the persistence of CAR-T. Contrastively, as the most commonly eliminated target in UCAR-T, TCR deficiency was found to be a key disadvantageous factor for the shorter-term anti-tumor efficacy in vivo. Our study demonstrated ETUCAR-T could effectively resist allogeneic NK rejection ex vivo and in vivo.DiscussionOur research provided a potential and effective strategy for promoting the persistence of UCAR-T cells in clinical application. And it reveals the potential key factors of the poor persistence of UCAR-T along with new insights for future development.</p