Cathepsin B-Ignited Nanorocket To Blast Tumor Lysosomes for TLR-Fortified Lysosomal Immunotherapy with Dual-Switchable Fluorescence/Magnetic Resonance Imaging

Abstract

<p>Immunotherapy based on immunogenic cell death (ICD) holds great promise for cancer treatment, but conventional ICD inducers often suffer from low specificity and limited tumor permeability, restricting their therapeutic effectiveness. Herein, a dual-switchable fluorescence (FL)/magnetic resonance imaging (MRI)-guided nanorocket (UIOQM-IQ) is meticulously designed to blast lysosomes through lysosomal cathepsin B (CTSB)-responsive nanoparticles aggregation, which can trigger lysosomal membrane permeabilization (LMP) to precisely induce ICD. This nanorocket consists of an ultrasmall iron oxide (UIO) nanoparticle conjugated with a CTSB-cleavable peptide, an aggregation-induced emission fluorophore QMTPA, and a Toll-like receptor 7/8 agonist imidazoquinoline (IQ). Upon arrival in the acidic tumor microenvironment, UIOQM-IQ initiates IQ release in a pH-dependent manner. Subsequently, CTSB in tumor lysosomes specifically cleaves the peptide within UIOQM to induce the concurrent release and aggregation of QMTPA and UIO nanoparticles. The aggregation of QMTPA activates a FL “off-on” switch to significantly improve tumor visualization, while UIO aggregates induce a distinct MRI contrast shift from T1 to T2, enabling deep-tissue imaging and real-time monitoring of nanoparticles aggregation. Notably, bulky UIO aggregates within lysosomes lead to elevated osmotic pressure, disrupting lysosomal integrity and eliciting LMP-induced ICD (LICD) through activating the ferroptosis pathway. This LICD strategy markedly enhances tumor immunogenicity and potentiates antigen presentation to realize lysosomal immunotherapy. Meanwhile, IQ synergistically augments immune activation through effective stimulation of antigen-presenting cells. Overall, this CTSB-ignited nanorocket addresses critical limitations of traditional ICD inducers and integrates dual-switchable FL/MR imaging with targeted immune activation, thereby offering a clinically promising strategy for advanced imaging-guided cancer immunotherapy.</p>