Developing multicolor upconversion nanoparticles (UCNPs) with the capability of regulating their emission wavelengths in the UV to visible range in response to external stimuli can offer more dynamic platforms for applications in high resolution bio-imaging, multicolor barcoding and driving multiple important photochemical reactions, such as photoswitching. In this communication, we have rationally designed single crystal core-shell structured UCNPs which are capable of orthogonal UV and visible emissions in response to two distinct NIR excitations at 808 and 980 nm. The orthogonal excitation-emission properties of such UCNPs, as well as their ability to utilize low power excitation, which attenuates any local heating from the lasers, endows the UCNPs with great potential for applications in materials and biological settings. As a proof of concept, the use of this UCNP for the efficient regulation of the two-way photoswitching of spiropyran by using dual wavelengths of NIR irradiation has been demonstrated.

Stimuli-responsive drug delivery vehicles have garnered immense interest in recent years due to unparalleled progress made in material science and nanomedicine. However, the development of stimuli-responsive devices with integrated real-time monitoring capabilities is still in its nascent stage because of the limitations of imaging modalities. In this paper, we describe the development of a polypeptide-wrapped mesoporous-silica-coated multicolor upconversion nanoparticle (UCNP@MSN) as an adenosine triphosphate (ATP)-responsive drug delivery system (DDS) for long-term tracking and real-time monitoring of drug release. Our UCNP@MSN with multiple emission peaks in UV-NIR wavelength range was functionalized with zinc-dipicolylamine analogue (TDPA-Zn2+) on its exterior surface and loaded with small-molecule drugs like chemotherapeutics in interior mesopores. The drugs remained entrapped within the UCNP-MSNs when the nanoparticles were wrapped with a compact branched polypeptide, poly(Asp-Lys)-b-Asp, because of multivalent interactions between Asp moieties present in the polypeptide and the TDPA-Zn2+ complex present on the surface of UCNP-MSNs. This led to luminescence resonance energy transfer (LRET) from the UCNPs to the entrapped drugs, which typically have absorption in UV–visible range, ultimately resulting in quenching of UCNP emission in UV–visible range while retaining their strong NIR emission. Addition of ATP led to a competitive displacement of the surface bound polypeptide by ATP due to its higher affinity to TDPA-Zn2+, which led to the release of the entrapped drugs and subsequent elimination of LRET. Monitoring of such ATP-triggered ratiometric changes in LRET allowed us to monitor the release of the entrapped drugs in real-time. Given these results, we envision that our proposed UCNP@MSN-polypeptide hybrid nanoparticle has great potential for stimuli-responsive drug delivery as well as for monitoring biochemical changes taking place in live cancer and stem cells.

Non-destructive neurotransmitter detection and real-time monitoring of stem cell differentiation are both of great significance in the field of neurodegenerative disease and regenerative medicine.Although luminescent biosensing nanoprobes have been developed to address this need, they have intrinsic limitations such as autofluorescence, scattering, and phototoxicity. However, upconversion nanoparticles (UCNPs) have gained increasing attention for various biomedical applications due to their high photo-stability, low auto-fluorescent background, and deep tissue penetration; however, UCNPs also suffer from low emission intensities due to undesirable energy migration pathways. To

organoids should exhibit essential features, including organ-specific multiple cell types, functions of the organ, and spatially organized structures. The emergence and progression of organoid technologies have resulted from several important discoveries (Figure 1). The formation of actual tissuelike colonies in vitro was firstly observed from a co-culture system of keratinocytes and 3T3 fibroblasts. [4] Self-organization, one of the fundamental aspects of organogenesis, was first observed via two distinct approaches, namely reaggregation and structural patterning of dissociated single cells. [5,6] The establishment of 3D culture methods for the structural organization began with the development of extracellular matrices (ECM).In the late 1980s, Bissell and colleagues observed that a laminin-rich gel could function as a basement membrane to differentiate and morphogenesis of mammary epithelial cells. [7,8] In the 1990s, it was reported that in addition to their primary role in physical support, ECM components could regulate gene expression by interacting with integrin-based focal adhesion pathways. [9] Finally, in 2009, Clevers group reported that embedding single intestinal stem cells in ECM substitute had created crypt-like structures similar to the epithelium of the native intestinal tissues, which were the first organoids. [10] Based on these recognitions, biochemical cues that include the initiation of lineage-specific genetic programs have been incorporated in 3D organoid cultures. Through exposure to morphogens, growth factors, or morphogen inhibitors, multiple research groups rapidly developed various organoid models using embryonic stem cells (ESCs) or adult stem cells (ASCs); these include intestine, [10] stomach, [11] liver, [12] pancreas, [13] prostate, [14] and brain [15] organoids. At the same time, vascularization techniques were devised by several groups to embody microenvironments that are physiologically close to their actual counterparts. Microfluidic systems, [16] endothelial cell-coated modules, [17] and vascular endothelial growth factor delivery systems [18] have been demonstrated as in vitro vasculature systems that can facilitate oxygen or nutrients transport to the inner mass of organoids.In the late 2010s, owing to the accumulated information on mechanisms underlying organogenesis and the remarkable advancements in the fields of biomaterial and bioengineering, the era of "organoid customization" has begun. Customizable hydrogel matrices have been proposed to form intestinal organoids whose internal networks recapitulate the Recent advances in 3D cell culture technology have enabled scientists to generate stem cell derived organoids that recapitulate the structural and functional characteristics of native organs. Current organoid technologies have been striding toward identifying the essential factors for controlling the processes involved in organoid development, including physical cues and biochemical signaling. There is a growing demand for engineering dynamic niches characterized by ...

Current stem cell therapy suffers low efficiency in giving rise to differentiated cell lineages, which can replace the original damaged cells. Nanomaterials, on the other hand, provide unique physical size, surface chemistry, conductivity, and topographical microenvironment to regulate stem cell differentiation through multidimensional approaches to facilitate gene delivery, cell–cell, and cell–ECM interactions. In this review, nanomaterials are demonstrated to work both alone and synergistically to guide selective stem cell differentiation. From three different nanotechnology families, three approaches are shown: (1) soluble microenvironmental factors; (2) insoluble physical microenvironment; and (3) nano-topographical features. As regenerative medicine is heavily invested in effective stem cell therapy, this review is inspired to generate discussions in the potential clinical applications of multi-dimensional nanomaterials.

Light-mediated remote control of stem cell fate, such as proliferation, differentiation, and migration, can bring a significant impact on stem cell biology and regenerative medicine. Current UV/vis-mediated control approaches are limited in terms of nonspecific absorption, poor tissue penetration, and phototoxicity. Upconversion nanoparticle (UCNP)-based near-infrared (NIR)-mediated control systems have gained increasing attention for vast applications with minimal nonspecific absorption, good penetration depth, and minimal phototoxicity from NIR excitations. Specifically, 808 nm NIR-responsive upconversion nanomaterials have shown clear advantages for biomedical applications owing to diminished heating effects and better tissue penetration. Herein, a novel 808 nm NIR-mediated control method for stem cell differentiation has been developed using multishell UCNPs, which are optimized for upconverting 808 nm NIR light to UV emission. The locally generated UV emissions further toggle photoswitching polymer capping ligands to achieve spatiotemporally controlled small-molecule release. More specifically, with 808 nm NIR excitation, stem cell differentiation factors can be released to guide neural stem cell (NSC) differentiation in a highly controlled manner. Given the challenges in stem cell behavior control, the developed 808 nm NIR-responsive UCNP-based approach to control stem cell differentiation can represent a new tool for studying single-molecule roles in stem cell and developmental biology.

Photoactivatable fluorophores are essential tools for studying the dynamic molecular interactions within important biological systems with high spatiotemporal resolution. However, currently developed photoactivatable fluorophores based on conventional dyes have several limitations including reduced photoactivation efficiency, cytotoxicity, large molecular size, and complicated organic synthesis. To overcome these challenges, we herein report a class of photoactivatable fluorescent N-hydroxyoxindoles formed through the intramolecular photocyclization of substituted o-nitrophenyl ethanol (ONPE). These oxindole fluorophores afford excellent photoactivation efficiency with ultra-high fluorescence enhancement (up to 800-fold) and are small in size. Furthermore, the oxindole derivatives show exceptional biocompatibility by generating water as the only photolytic side product. Moreover, structure–activity relationship analysis clearly revealed the strong correlation between the fluorescent properties and the substituent groups, which can serve as a guideline for the further development of ONPE-based fluorescent probes with desired photophysical and biological properties. As a proof-of-concept, we demonstrated the capability of a new substituted ONPE that has an uncaging wavelength of 365–405 nm and an excitation/emission at 515 and 620 nm, for the selective imaging of a cancer cell line (Hela cells) and a human neural stem cell line (hNSCs).

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