Upconversion nanomaterials and delivery systems for smart photonic medicines and healthcare devices

Abstract

In the past decade, upconversion (UC) nanomaterials have been extensively investigated for the applications to photomedicines with their unique features including biocompatibility, near-infrared (NIR) to visible conversion, photostability, controllable emission bands, and facile multi-functionality. These characteristics of UC nanomaterials enable versatile light delivery for deep tissue biophotonic applications. Among various stimuli-responsive delivery systems, the light-responsive delivery process has been greatly advantageous to develop spatiotemporally controllable on-demand “smart” photonic medicines. UC nanomaterials are classified largely to two groups depending on the photon UC pathway and compositions: inorganic lanthanide-doped UC nanoparticles and organic triplet–triplet annihilation UC (TTA-UC) nanomaterials. Here, we review the current-state-of-art inorganic and organic UC nanomaterials for photo-medicinal applications including photothermal therapy (PTT), photodynamic therapy (PDT), photo-triggered chemo and gene therapy, multimodal immunotherapy, NIR mediated neuromodulations, and photochemical tissue bonding (PTB). We also discuss the future research direction of this field and the challenges for further clinical development.

Introduction

A variety of photonic nanomaterials have been developed for photomedicines including light-responsive and light-emitting nanomaterials such as quantum dots (QDs), Au nanomaterials, Ag nanomaterials, polymeric nanoparticles (NPs), organic dyes, 2D materials, and transition metal chalcogenides [1]. These nanomaterials have unique optical properties by the quantum confinement effect with the multi-energy levels of nanomaterials. However, they have several critical issues for biomedical applications such as the low penetration depth of excitation light, photobleaching, and low biocompatibility. In general, most of the photonic nanomaterials have an emission wavelength longer than the excitation wavelength according to the Stokes' law. In contrast, anti-Stokes-type luminescence materials have a shorter wavelength with higher energy photons than those of the excitation wavelength [2], [3], [4], [5]. Since this concept has been firstly proposed by Nicolaas Bloembergen in 1959 [6], upconversion (UC) nanomaterials have been widely investigated for photonic devices [7], energy harvesting [8], security [9], and biomedical applications [1]. Especially, UC nanomaterials can be served as a versatile light delivery agent for various photomedicines due to the near-infrared (NIR) to visible light conversion for the deep-tissue penetration with photostability and biocompatibility.

There are two main categories of UC nanomaterials accoridng to the photon UC pathways and compositions: inorganic lanthanide-doped UCNPs and organic triplet–triplet annihilation UC (TTA-UC) nanomaterials. Inorganic lanthanide-doped UCNPs trigger photon UC via the long-lived multiple electronic states of doped lanthanide ions. They have unique optical properties such as photon UC with low photobleaching, large anti-Stokes shifts, controllable emission bands, biocompatibility, ease of multifunctionality, facile size control, and phase tunability, and long-term photostability [10], [11], [12], [13], [14], [15]. UCNPs have emerged as functional materials for various biomedical applications including multimodal bioimaging [16], [17], [18], molecular sensing [19], [20], photomedicine [21], [22], [23], and optical security [24], [25], [26], [27]. In contrast, organic TTA-UC systems rely on the annihilation process of two triplet excitation photons to one higher energy photon. In the TTA-UC systems, TTA is achieved through an organic-based photosensitizer and acceptor to generate UC photons. All TTA-UCs are composed of sensitizer, acceptor, and media in which both materials are dissolved, and their physicochemical properties are important factors for UC feasibility, quantum efficiency, photostability, and energy shifting degree. TTA-UC has exhibited outstanding characteristics such as intense absorption coefficient of sensitizers, high quantum yield (QY), and concomitant low power density excitation source. However, it suffers from the limitation of low biocompatibility, small anti-Stokes shift, and low stability in vivo [2].

In this review, we describe an overview of UC nanomaterials and their current-state-of-the-art photomedical applications such as photothermal therapy (PTT), photodynamic therapy (PDT), photo-triggered chemo- and gene-therapy, multimodal immunotherapy, NIR-mediated neuromodulations, and photochemical tissue bonding (PTB). Fig. 1 shows the schematic illustration of upconversion nanomaterials for biomedical photonic applications with the main conceptual process in each application. On top of that, we discuss the design criteria of UC nanomaterials for specific biophotonic applications, providing the future perspectives on the challenges, strategies to overcome, and feasibility for further clinical applications.