The Convergence of Sonodynamic Therapy and Cuproptosis in the Dual-Responsive Biomimetic CytoNano for Precision Mitochondrial Intervention in Cancer Treatment.

The integration of sonodynamic therapy (SDT) with cuproptosis for targeted cancer treatment epitomizes a significant advancement in oncology. Herein, we present a dual-responsive therapeutic system, "CytoNano", which combines a cationic liposome infused with copper-nitride nanoparticles and oxygen-rich perfluorocarbon (Lip@Cu3N/PFC-O2), all enveloped in a biomimetic coating of neutrophil membrane and acid-responsive carboxymethylcellulose. CytoNano leverages the cellular mimicry of neutrophils and acid-responsive materials, enabling precise targeting of tumors and their acidic microenvironment. This strategic design facilitates the targeted release of Lip@Cu3N/PFC-O2 within the tumor, enhancing cancer cell uptake and mitochondrial localization. Consequently, it amplifies the therapeutic efficacy of both Cu3N-driven SDT and cuproptosis while preserving healthy tissues. Additionally, CytoNano's ultrasound responsiveness enhances intratumoral oxygenation, overcoming physiological barriers and initiating a combined sonodynamic-cuproptotic effect that induces multiple cell death pathways. Thus, we pioneer a biomimetic approach in precise sonodynamic cuproptosis, revolutionizing cancer therapy.

Cellular Trojan Horse initiates bimetallic Fe-Cu MOF-mediated synergistic cuproptosis and ferroptosis against malignancies.

Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.

Bioengineered Neutrophils for Smart Response in Brain Infection Management.

Brain infections, frequently accompanied by significant inflammation, necessitate comprehensive therapeutic approaches targeting both infections and associated inflammation. A major impediment to such combined treatment is the blood-brain barrier (BBB), which significantly restricts therapeutic agents from achieving effective concentrations within the central nervous system. Here, a neutrophil-centric dual-responsive delivery system, coined "CellUs," is pioneered. This system is characterized by live neutrophils enveloping liposomes of dexamethasone, ceftriaxone, and oxygen-saturated perfluorocarbon (Lipo@D/C/P). CellUs is meticulously engineered to co-deliver antibiotics, anti-inflammatory agents, and oxygen, embodying a comprehensive strategy against brain infections. CellUs leverages the intrinsic abilities of neutrophils to navigate through BBB, accurately target infection sites, and synchronize the release of Lipo@D/C/P with local inflammatory signals. Notably, the incorporation of ultrasound-responsive perfluorocarbon within Lipo@D/C/P ensures the on-demand release of therapeutic agents at the afflicted regions. CellUs shows considerable promise in treating Staphylococcus aureus infections in mice with meningitis, particularly when combined with ultrasound treatments. It effectively penetrates BBB, significantly eliminates bacteria, reduces inflammation, and delivers oxygen to the affected brain tissue, resulting in a substantial improvement in survival rates. Consequently, CellUs harnesses the natural chemotactic properties of neutrophils and offers an innovative pathway to improve treatment effectiveness while minimizing adverse effects.

Solution-based fabrication of mechanically transformative materials for implantable applications.

Implantable probes and needles represent multifunctional biomedical platforms by integrating sensing, stimulation, and drug delivery capabilities. Conventional rigid probes often result in inflammatory responses due to large mechanical mismatch with soft biological tissues, whereas soft probes with improved long-term performances are difficult to be inserted deep into the compliant biological tissues. An emerging class of mechanically transformative materials addresses the challenge by embedding a phase-change material of gallium within an elastomeric matrix. These materials exhibit high stiffness under ambient conditions to enable facile insertion and compliant mechanical properties after implantations. The widespread implementation of mechanically transformative materials is primarily hindered by the lack of facile fabrication techniques for delicate gallium features. In this study, we introduce a solution-based approach for scalable fabrication of gallium-based mechanically transformative materials, which exhibit bistable mechanical properties with large modulations in the modulus by five orders of magnitude. In a solution-based coating process, gallium features are created based on a patterned copper film and then encapsulated with elastomers to form mechanically transformative materials. The height profile of the gallium feature is controlled by the two-dimensional design of the copper pattern, which provides access to delicate and complex three-dimensional features as exemplified by mechanically transformative indwelling needles with sharp tips. The practical suitability is demonstrated by the in vivo implementation of the indwelling needles for long-term chemotherapy. The excellent biocompatibility enables applications of mechanically transformative biomedical devices in chronic implantable systems.

A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance.

Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.

A one-pot modular assembly strategy for triple-play enhanced cytosolic siRNA delivery.

Robust efficiency for cytosolic small interfering RNA (siRNA) delivery is of great importance for effective gene therapy. To significantly improve the cytosolic siRNA delivery, a "one-pot modular assembly" strategy is developed to assemble a triple-play enhanced cytosolic siRNA delivery system via a facile and innocuous copper-free click reaction. Specifically, three modules are prepared including octreotide for receptor-mediated endocytosis, a cell-penetrating peptide (CPP) for cell penetration, and glutamic acid for the charge-reversal property. All three modules with distinct facilitating endocytosis effects are expediently assembled on the surface of the siRNA/liposome complex to fabricate a multifunctional integrated siRNA delivery system (OCA-CC). OCA-CC has been demonstrated to have enhanced cytosolic delivery and superior gene-silencing efficiency in multiple tumor cells due to the combined effects of all the three modules. High levels of survivin-silencing are also achieved by OCA-CC on orthotopic human breast cancer (MCF-7)-bearing mice accompanied by significant tumor inhibition. This research provides a facile strategy to produce safe and tunable siRNA delivery systems for effective gene therapy and to facilitate the development of multifunctional siRNA vectors.