Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system ([email protected]) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.

MXenes, a new class of two‐dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W_1.33C i‐MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in‐plane ordered (W_2/3Y_1/3)₂AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W_1.33C i‐MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W_1.33C i‐MXene possesses a strong predominance of near‐infrared (NIR) absorbance. The constructed ultrathin W_1.33C nanosheets feature excellent photothermal‐conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal‐imaging properties and photothermal‐ablation performance of W_1.33C‐BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W_1.33C‐BSA nanosheets‐induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i‐MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.

Tumor targeting and effective immunomodulation are of critical significance during tumor treatment by sonodynamic therapy (SDT). Herein, the probiotic engineering of the clinically approved sonosensitizer (hematoporphyrin monomethyl ether (HMME)) is reported onto the probiotic bacterium Bifidobacteria Longum (BiL) for sonosensitive bifidobacterium construction (HMME@BiL cells). Based on the hypoxic tropism feature of the strain, effective tumor‐targeted sonodynamic therapeutics can be achieved both in vitro and in vivo. To improve the immunological responses against tumor during sonodynamics, a recently‐developed stimulator of interferon genes immune agonist SR717 has been employed to improve the anti‐tumor immunity with prominent activities, eradicating both primary and metastatic tumors with high efficiency and satisfied biocompatibility. The present work provides a promising paradigm of microbiotic nanomedicine in a sophisticated sonoimmunotherapeutic strategy against malignant tumors.

Biomarkers (e.g., acidity, H₂O₂, hypoxia, and specific molecules) as one primary component of tumor microenvironments are closely associated with occurrence, invasion, and metastasis of malignancy, thus can act as biological targets. However, their monitoring remains a challenging task. Herein, a coordination‐dependent longitudinal relaxation tuning (CLRT) that occurs between a Mn²⁺ “donor” and a Mn²⁺ “acceptor” is established to enable biological target sensing. Relying on the differences of coordination ability and spatial structure between donors and acceptors, the biological targets as Mn²⁺ acceptor can take Mn²⁺ away from the donors (i.e., modified ligands) in nanoscale probes, which consequently varies T1‐weighted (T1W) magnetic resonance imaging (MRI) signal. The coordination ability and spatial structure of the modified Mn²⁺ “donor” and the pore diameter of donor carrier are demonstrated to determine the feasibility, specificity, and generality of CLRT. With CLRT, this MRI‐based ruler is demonstrated for the successful specific detection of biological targets (i.e., hyaluronic acid and glutathione) of malignancy, and its potential in quantitative measurement of hyaluronic acid is further demonstrated. CLRT can serve as a novel and general sensing principle to augment the exploration of a wide range of biological systems.