Abstract Cancer stem cells (CSCs) possess a high degree of plasticity, constituting a formidable challenge to identify and screen CSCs in situ with outstanding specificity and sensitivity. To overcome this limitation, a self‐assembled heterodimer consisting of clustered regularly interspaced short palindromic repeats/Cas12a (named A‐CCA) linkage is designed for in situ identification and screening of gastric CSCs (GCSCs) from gastric cancer cells (GCCs). In this system, the editable character of crRNA performs recognition of dual‐targets in GCSCs, effectively boosting the specificity of identification, while the enzymatic reaction of Cas12a contributes meaningfully to the sensitivity of sensing, enabling in situ examination and screening of GCSCs. Specifically, the A‐CCA nanoplatforms hybridized with ABCG 2 and ABCB 1 overexpress in GCSCs, which can generate heterodimers and simultaneously restore the function of trans ‐cleavage. At this time, the asymmetry of the heterodimer causes a circular dichroism signal, which together with the recovered fluorescence signal form a dual‐signals output system that can further ensure the precision of screening GCSC. Therefore, fluorescence‐enhanced GCSCs can be sorted out from GCCs by flow cytometry. Furthermore, GCSCs screened by this assay possess extremely aggressive tumorigenic efficiency, providing a fundamental research object for further developing CSC targeted drugs in vivo.
Abstract An effective dose at specific sites is of paramount importance for disease therapy. While therapeutic reagents such as small molecule drugs, nucleic acids, peptides, and proteins are suffered from degradation or clearance by physiological environment, nanomedicine has emerged to improve drug delivery efficiency due to their superior targeting ability. By tailoring the properties of nanoparticle, including size, shape, surface chemistry, site‐specific drug delivery in organ, cellular, and subcellular level could be achieved. This minireview highlights recent advances in the development of targeted drug delivery system for disease therapy.
Fluorescent nanosensors have been widely applied in recognition and imaging of bioactive small molecules; however, the complicated surface modification process and background interference limit their applications in practical biological samples. Here, a simple, universal method was developed for ratiometric fluorescent determination of general small molecules. Taking superoxide anion (O2•–) as an example, the designed sensor was composed of three main moieties: probe carrier, rattle-type silica colloidal particles (mSiO2@hmSiO2 NPs); reference fluorophore doped into the core of NPs, fluorescein isothiocyanate (FITC); fluorescent probe for superoxide anion, hydroethidine (HE). In the absence of O2•–, the sensor just emitted green fluorescence of FITC at 518 nm. When released HE was oxidized by O2•–, the oxidation product exhibited red fluorescence at 570 nm and the intensity was linearly associated with the concentration of O2•–, while that of reference element remained constant. Accordingly, ratiometric determination of O2•– was sensitively and selectively achieved with a linear range of 0.2–20 μM, and the detection limit was calculated as low as 80 nM. Besides, the technique was also successfully applied for dual-emission imaging of O2•– in live cells and realized visual recognition with obvious fluorescence color change in normal conditions or under oxidative stress. As long as appropriate reference dyes and sensing probes are selected, ratiometric biosensing and imaging of bioactive small molecules would be achieved. Therefore, the design could provide a simple, accurate, universal platform for biological applications.
In article number 2100629, Liping Jiang, Jun-Jie Zhu, Zhen Gu and co-workers develop a lipid-droplet-based drug delivery system for cancer photodynamic therapy. The lipid droplet, which is derived from adipocytes, is leveraged to potentiate the anticancer efficacy of the lipid-conjugated drug.
Abstract Abnormal tumor microenvironment (TME) facilitates tumor proliferation and metastasis and establishes physiological barriers for effective transport of therapeutics inside the tumor, posing great challenges for cancer treatment. We designed a core‐satellite size transformable nanoframework (denoted as T‐PFRT) that can synchronously adapt to and remold TME for augmenting photodynamic therapy to inhibit tumor growth and prevent tumor metastasis. Upon matrix metalloproteinase 2 (MMP2)‐responsive dissociation of the nanoframework in TME, the core structure loaded with TGFβ signaling pathway inhibitor and oxygen‐carrying hemoglobin aims to stroma remodeling and hypoxia relief, allowing photosensitizer‐encapsulated satellite particles to penetrate to deep‐seated tumor for oxygen‐fueled photodynamic therapy. T‐PFRT could overcome the stroma and hypoxia barriers for delivering therapeutics and gain excellent therapeutic outcomes in the treatment of primary and metastatic tumors.
Cutting off the glucose supply by glucose oxidase (GOx) has been regarded as an emerging strategy in cancer starvation therapy. However, the standalone GOx delivery suffered suboptimal potency for tumor elimination and potential risks of damaging vasculatures and normal organs during transportation. To enhance therapeutic efficacy and tumor specificity, a site-specific activated dual-catalytic nanoreactor was herein constructed by embedding GOx and ferrocene in hyaluronic acid (HA)-enveloped dendritic mesoporous silica nanoparticles to promote intratumoral oxidative stress in cancer starvation. In this nanoreactor, the encapsulated GOx served as the primary catalyst that accelerated oxidation of glucose and generation of H2O2, while the covalently linked ferrocene worked as the secondary catalyst for converting the upstream H2O2 to more toxic hydroxyl radicals (•OH) via a classic Fenton reaction. The outmost HA shell not only offered a shielding layer for preventing blood glucose from oxidation during nanoreactor transportation, thus minimizing the probable oxidative damage to normal tissues, but also imparted the nanoreactor with targeting ability for facilitating its internalization into CD44-overexpressing tumor cells. After the nanoreactor was endocytosed by target cells, the HA shell underwent hyaluronidase-triggered degradation in lysosomes and switched on the cascade catalytic reaction mediated by GOx and ferrocene. The resulting glucose exhaustion and •OH accumulation would effectively kill cancer cells and suppress tumor growth via combination of starvation and oxidative stress enhancement. Both in vitro and in vivo results indicated the significantly amplified therapeutic effects of this synergistic therapeutic strategy based on the dual-catalytic nanoreactor. Our study provides a new avenue for engineering therapeutic nanoreactors that take effect in a tumor-specific and orchestrated fashion for cancer starvation therapy.
Since the launch of the Alliance for Nanotechnology in Cancer by the National Cancer Institute in late 2004, several similar initiatives have been promoted all over the globe with the intention of advancing the diagnosis, treatment and prevention of cancer in the wake of nanoscience and nanotechnology. All this has encouraged scientists with diverse backgrounds to team up with one another, learn from each other, and generate new knowledge at the interface between engineering, physics, chemistry and biomedical sciences. Importantly, this new knowledge has been wisely channeled towards the development of novel diagnostic, imaging and therapeutic nanosystems, many of which are currently at different stages of clinical development. This roadmap collects eight brief articles elaborating on the interaction of nanomedicines with human biology; the biomedical and clinical applications of nanomedicines; and the importance of patient stratification in the development of future nanomedicines. The first article reports on the role of geometry and mechanical properties in nanomedicine rational design; the second articulates on the interaction of nanomedicines with cells of the immune system; and the third deals with exploiting endogenous molecules, such as albumin, to carry therapeutic agents. The second group of articles highlights the successful application of nanomedicines in the treatment of cancer with the optimal delivery of nucleic acids, diabetes with the sustained and controlled release of insulin, stroke by using thrombolytic particles, and atherosclerosis with the development of targeted nanoparticles. Finally, the last contribution comments on how nanomedicine and theranostics could play a pivotal role in the development of personalized medicines. As this roadmap cannot cover the massive extent of development of nanomedicine over the past 15 years, only a few major achievements are highlighted as the field progressively matures from the initial hype to the consolidation phase.
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