Intracellular Delivery of Therapeutic Protein via Ultrathin Layered Double Hydroxide Nanosheets.

The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable protein, gelonin, towards efficient and specific cancer treatment. The LDH nanosheet was synthesized via a facile method without using exfoliation agents and showed a high loading capacity of proteins (up to 182%). Using 2D and 3D 4T1 breast cancer cell models, LDH-gelonin demonstrated significantly higher cellular uptake efficiency, favorable endosome escape ability, and deep tumor penetration performance, leading to a higher anticancer efficiency, in comparison to free gelonin. This work provides a promising strategy and a generalized nanoplatform to efficiently deliver biofunctional proteins to unlock their therapeutic potential for cancer treatment.

Two-Dimensional Ultra-Thin Nanosheets with Extraordinarily High Drug Loading and Long Blood Circulation for Cancer Therapy.

Nanoparticle drug delivery is largely restricted by the low drug loading capacity of nanoparticle carriers. To address this critical challenge and maximize the potential of nanoparticle drug delivery, a 2D ultra-thin layered double hydroxide (LDH) nanosheet with exceptionally high drug loading, excellent colloidal stability, and prolonged blood circulation for cancer treatment is constructed. The nanosheet is synthesized via a biocompatible polymer-assisted bottom-up method and exhibits an ultra-thin 2D sheet-like structure that enables a considerable amount of cargo anchoring sites available for drug loading, leading to an extraordinary 734% (doxorubicin/nanoparticle mass ratio) drug loading capacity. Doxorubicin delivered by the nanosheet remains stable on the nanosheet carrier under the physiological pH condition, while showing sustained release in the tumor microenvironment and the intracellular environment, thus demonstrating on-demand drug release as a result of pH-responsive biodegradation of nanosheets. Using in vitro and in vivo 4T1 breast cancer models, the nanosheet-based ultra-high drug-loading system demonstrates even enhanced therapeutic performance compared to the multilayered LDH-based high drug-loading system, in terms of increased cellular uptake efficiency, prolonged blood circulation, superior therapeutic effect, and reduced systemic toxicity.

Disulfiram-loaded metal organic framework for precision cancer treatment via ultrasensitive tumor microenvironment-responsive copper chelation and radical generation.

Off-target toxicity remains a major limitation of current cancer therapy, necessitating an alternative precision approach to treat cancers. Herein, a tumor microenvironment (TME)-triggered anticancer strategy was developed by constructing an anti-alcoholism drug disulfiram (DSF)-loaded, Cu-doped zeolite imidazolate frameworks-8 (DSF-Cu/ZIF-8) nanoparticle followed by PEGylation (PEG-DSF-Cu/ZIF-8) to realize in situ generation of cytotoxic compounds specifically in TME. The PEG-DSF-Cu/ZIF-8 demonstrated excellent hydrolytic stability in normal physiological conditions, guaranteeing the minimized off-target release of disulfiram and Cu ions. Under the TME condition, the PEG-DSF-Cu/ZIF-8 exhibited acidity-triggered biodegradation and the associated payload release, through which low-toxic compounds (disulfiram and Cu2+ ions) were converted to highly cytotoxic Cu-chelate product to kill cells specifically in TME. Tumor-sensitive anti-cancer performance was further enhanced by hydroxyl radical generation via TME-responsive Fenton-like reactions catalyzed by Cu+ presenting in the PEG-DSF-Cu/ZIF-8 structure and Cu+ produced during formation of the chelate product. Anti-cancer therapeutic evaluation was performed in 2D 4T1 tumor cell culture and 3D 4T1 tumor spheroids, and demonstrated highly TME-responsive, low-dose induced anti-cancer effect. This proof-of-concept work provides a nanoparticle-based drug repurposing strategy by developing a tumor-sensitive anti-cancer agent for low-toxic and efficacious cancer therapy.

Chemotaxis-Driven 2D Nanosheet for Directional Drug Delivery toward the Tumor Microenvironment.

Micro/nanoscaled motor particles represent a group of intelligent materials that can precisely and rapidly respond to biological microenvironments and improve therapeutic outcomes. In order to maximize biomedical application potentials, developing a nanoscaled motor particle that is able to move autonomously toward a biological target is highly desired but still remains a critical challenge. Herein, a 2D nanosheet-based catalytic nanomotor with chemotaxis behavior is developed for enhanced drug delivery toward the tumor microenvironment. The nanomotors are constructed via a facile one-pot method and exhibit ultrathin monolayer nanosheet morphology. The 2D structure of nanomotors allows high catalytic activity, leading to responsive, sustained, and relatively long distance movement. Importantly, this nanomotor demonstrates directional motion toward the high gradient of H2 O2 fuel, exhibiting excellent chemotactic properties. After loading an anticancer drug doxorubicin, the nanomotor shows effective inhibition on cancer cell growth in simulated tumor microenvironments. The practical drug delivery application is further strengthened by the intracellular acidity-triggered biodegradability of the nanomotor after accomplishing the directional drug delivery function. This proof-of-concept work highlights the efficient catalytic activity, tumor microenvironment-guided chemotactic movement, excellent cellular performance of the 2D nanomotor, and opens an avenue for biomedical applications such as controlled and smart drug delivery.

Recent advances in improving tumor-targeted delivery of imaging nanoprobes.

Tumor-targeted delivery of imaging nanoprobes provides a promising approach for the precision imaging diagnosis of cancers. Nanoprobes with desired bio-nano interface properties can preferably enter tumor tissues through the vascular endothelium, penetrate into deep tissues, and detect target lesions. Surface engineering of nanoparticles offers a critical strategy to improve tumor-targeting capacities of nanoprobes. Improvements to the efficacy of targeted nanoprobes have been intensively explored and much of this work centers on the selection of suitable targeting ligands. Herein, in this review, various recent strategies based on different targeting ligands to improve tumor-targeting of imaging nanoprobes have been developed, ranging from small molecule ligands to biomimetic coatings, with highlights on emerging coating techniques using cell membranes and dual-targeting ligands. In particular, construction and surface modification methods, targeting capacities, and imaging/theranostic performance with key issues and potential questions have been described and discussed together with considerations for future development and innovations.