In-Tumor Biosynthetic Construction of Upconversion Nanomachines for Precise Near- Infrared Phototherapy

Targeted construction of therapeutic nanoplatforms in tumor cells with specific activation remains appealing but challenging. Here, we design a cancer-motivated upconversion nanomachine (UCNM) based on porous upconversion nanoparticles (p-UCNPs) for precise phototherapy. The nanosystem is equipped with a telomerase substrate (TS) primer and simultaneously encapsulates 5-aminolevulinic acid (5-ALA) and D-arginine (D-Arg). After coating with hyaluronic acid (HA), it can readily get into tumor cells, where 5-ALA induces efficient accumulation of protoporphyrin IX (PpIX) via the inherent biosynthetic pathway, and the overex-pressed telomerase prolonged the TS to form G-quadruplexes (G4) for binding the resulting PpIX as a nanomachine. This nanomachine can respond to near-infrared (NIR) light and promote the active singlet oxygen (1O2) production due to the efficiency of Fo''rster resonance energy transfer (FRET) between p-UCNPs and PpIX. Intriguingly, such oxidative stress can oxidize D-Arg into nitric oxide (NO), which relieves the tumor hypoxia and in turn improves the phototherapy effect. This in situ assembly approach significantly enhances targeting in cancer therapy and might be of considerable clinical value.

Automated summary

Researchers have designed a cancer-activated nanomachine based on porous upconversion nanoparticles for precise phototherapy. The nanosystem contains a telomerase substrate primer and encapsulates 5-aminolevulinic acid and D-arginine. After coating with hyaluronic acid, the nanomachine can easily enter tumor cells and induce efficient accumulation of protoporphyrin IX via biosynthetic pathway. The nanomachine can respond to near-infrared light and generate active singlet oxygen through Förster resonance energy transfer. Moreover, it can relieve tumor hypoxia by converting D-arginine into nitric oxide, thereby improving the phototherapy effect.