In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics

TLDR

Precision nanomedicines that direct nanostructure‑based reagents into tumour‑targeted areas face a critical challenge, but chemical reaction‑mediated localization in response to tumour microenvironment perturbations offers promising opportunities for rational design of effective nano‑theranostics. The study presents a microenvironment‑sensitive strategy to localize peptide‑premodified upconversion nanocrystals within tumour areas. Upon tumour‑specific cathepsin protease reactions, peptide cleavage induces covalent cross‑linking between exposed cysteine and 2‑cyanobenzothiazole on neighbouring particles, triggering accumulation of UCNs into tumour sites. Enzyme‑triggered cross‑linking enhances upconversion emission under 808 nm laser irradiation, amplifies singlet oxygen generation from attached photosensitizers, and leads to remarkable tumour inhibition via intratumoral or intravenous injection, offering a multimodal solution for molecular sensing and site‑specific tumour treatment.

Abstract

The development of precision nanomedicines to direct nanostructure-based reagents into tumour-targeted areas remains a critical challenge in clinics. Chemical reaction-mediated localization in response to tumour environmental perturbations offers promising opportunities for rational design of effective nano-theranostics. Here, we present a unique microenvironment-sensitive strategy for localization of peptide-premodified upconversion nanocrystals (UCNs) within tumour areas. Upon tumour-specific cathepsin protease reactions, the cleavage of peptides induces covalent cross-linking between the exposed cysteine and 2-cyanobenzothiazole on neighbouring particles, thus triggering the accumulation of UCNs into tumour site. Such enzyme-triggered cross-linking of UCNs leads to enhanced upconversion emission upon 808 nm laser irradiation, and in turn amplifies the singlet oxygen generation from the photosensitizers attached on UCNs. Importantly, this design enables remarkable tumour inhibition through either intratumoral UCNs injection or intravenous injection of nanoparticles modified with the targeting ligand. Our strategy may provide a multimodality solution for effective molecular sensing and site-specific tumour treatment.