Skin
interstitial fluid (ISF) containing a great variety of molecular
biomarkers derived from cells and subcutaneous blood capillaries has
recently emerged as a clinically potential component for early diagnosis
of a wide range of diseases; however, the minimally invasive sampling
and detection of cell-free biomarkers in ISF is still a key challenge.
Herein, we developed microneedles (MNs) that consist of gelatin methacryloyl
(GelMA) and graphene oxide (GO) for the enrichment and sensitive detection
of multiple microRNA (miRNA) biomarkers from skin ISF. The GO-GelMA
MNs exhibited robust mechanical properties, fast sampling kinetics,
and large swelling capacity, which enabled collecting ISF volume high
to 21.34 μL in 30 min, facilitating effective miRNA analysis.
It preliminarily realized the sensitive detection of three types of
psoriasis-related miRNAs biomarkers either on the patch itself or
in solution after release from the hydrogel by combining catalytic
hairpin assembly signal amplification reaction. The automated and
minimally invasive ISF miRNA detection technology of GO-GelMA MNs
has great potential to monitor cell-free clinically informative biomarkers
for personalized diagnosis and prognosis.
DNAzyme shows great promise in designing a highly sensitive
and
specific sensing platform; however, the low cellular uptake efficiency,
instability, and especially the insufficient cofactor supply inhibit
the intracellular molecule sensor applications. Herein, we demonstrate
a novel type of DNAzyme-based self-driven intracellular sensor for
microRNA (miRNA) detection in living cells. The sensor consists of
a metal–organic framework [zeolite imidazole framework (ZIF-8)]
core loaded with a shell consisting of a rationally designed DNAzyme,
where the substrate strand is modified with FAM and BHQ-1 nearby both
the sides of the restriction site, respectively, while the enzyme
strand consists of two separate strands with a complementary fragment
to the substrate strand and the targeting miRNA, respectively. The
ZIF-8 nanoparticles enable the efficient delivery of DNAzyme into
the cell and protect the DNAzyme from degradation. The pH-responsive
ZIF-8 degradation is accompanied with the release of the DNAzyme and
Zn2+ cofactors, and the intracellular target miRNAs recognize
and activate the DNAzyme driven by the Zn2+ cofactors to
cleave the substrate strand, resulting in the release of the FAM-labeled
shorter product strand and increased fluorescence for miRNA detection.
The self-driven approach can be generally applied to various miRNAs’
detection through DNAzyme engineering.
A cyanine fluorophore 2‐[4‐N,N‐diphenylaminostyryl]‐β‐naphthothiazolium propylsulfonate, N3, was synthesized. The asymmetric probe N3 displayed aggregation‐induced emission (AIE) characteristic in DMSO/H2O mixtures, whereas it presented twisted intra‐molecular charge transfer (TICT) non‐emissive state in Dioxane/H2O (Diox/H2O) mixtures. Both the AIE and TICT state could be modulated by proteins, exhibiting switch effect. In DMSO/H2O mixtures with 90% water fractions (fw), protein molecules adsorbed upon the aggregated crystalline nanoparticles of N3 and spread over the surface, thus the strong fluorescence emission of N3 was quenched. The different degree of quenching among proteins revealed that the adsorption of proteins on N3 aggregate particles arose from both hydrophobic and electrostatic interactions. The quenched ratio (I0/I) vs the concentration of positively protein lysozyme (Lys) gave a Langmuir type curve. In Diox/H2O mixtures with 90% fw, the addition of bovine serum albumin (BSA) led to the reduction of non‐emissive TICT state and made the fluorescence emission of N3 switch on. The large difference of N3 fluorescence emission toward BSA over other proteins including human serum albumin allowed us to establish a sensitive probe for BSA. An ON‐OFF and OFF‐ON dual‐modal red‐emitting fluorescence probe for proteins was established.
Optically active nanostructures consisting of organic compounds and metallic support have shown great promise in phototherapy due to their increased light absorption capacity and high energy conversion. Herein, we conjugated chlorophyll (Chl) to vanadium carbide (V2C) nanosheets for combined photodynamic/photothermal therapy (PDT/PTT), which reserves the advantages of each modality while minimizing the side effects to achieve an improved therapeutic effect. In this system, the Chl from Leptolyngbya JSC-1 extracts acted as an efficient light-harvest antenna in a wide NIR range and photosensitizers (PSs) for oxygen self-generation hypoxia-relief PDT. The available large surface of two-dimensional (2D) V2C showed high Chl loading efficiency, and the interaction between organic Chl and metallic V2C led to energy conversion efficiency high to 78%. Thus, the Chl/ V2C nanostructure showed advanced performance in vitro cell line killing and completely ablated tumors in vivo with 100% survival rate under a single NIR irradiation. Our results suggest that the artificial optical Chl/V2C nanostructure will benefit photocatalytic tumor eradication clinic application.
Graphical Abstract
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