We describe the development of a versatile fluorescence resonance energy transfer (FRET)-based real-time monitoring system, consisting of (a) coumarin-labeled-cysteine tethered mesoporous silica nanoparticles (MSNs) as the drug carrier, (b) a fluorescein isothiocyanate-β-cyclodextrin (FITC-β-CD) as redox-responsive molecular valve blocking the pores, and (c) a FRET donor-acceptor pair of coumarin and FITC integrated within the pore-unlocking event, thereby allowing for monitoring the release of drugs from the pores in real-time. Under non-reducing conditions, when the disulfide bond is intact, the close proximity between coumarin and FITC on the surface of MSNs results in FRET from coumarin to FITC. However, in the presence of the redox stimuli like glutathione (GSH), the disulfide bond is cleaved which leads to the removal of molecular valve (FITC-β-CD), thus triggering drug release and eliminating FRET. By engineering such a FRET-active donor-acceptor structure within the redox-responsive molecular valve, we can monitor the release of the drugs entrapped within the pores of the MSN nanocarrier, following the change in the FRET signal. We have demonstrated that, any exogenous or endogenous change in the GSH concentration will result in a change in the extent of drug release as well as a concurrent change in the FRET signal, allowing us to extend the applications of our FRET-based MSNs for monitoring the release of any type of drug molecule in real-time.

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.