A Smart Responsive Nanotheranostic System for MRI of Tumor Response to Immunotherapy and Enhanced Synergism of Thermo-Immunotherapy

The challenges associated with the assessment of immune checkpoint inhibitor (ICI) therapy and low immunotherapy response observed in patients with poorly immunogenic tumors are addressed. A smart-responsive nanoprobe MZF@Gd is synthetized based on magnetic resonance tuning (MRET). The nanoprobe is designed to be targeted and cleaved by granzyme B, a marker of cytotoxic T-cell activation. MZF@Gd consisted of superparamagnetic Mn- and Zn-doped ferrite magnetic nanoparticles (MZF-MNPs) with a magnetocaloric effect and a paramagnetic contrast agent gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA). These components are connected by the granzyme B substrate peptides. The activation of the T1WI signal through MRET, following the cleavage of the probe by granzyme B, enabled the accurate evaluation of the ICI therapeutic effect. Subsequently, an active-targeting magnetothermally responsive nanotheranostic agent FA-P(MZF@Gd/JQ1) is fabricated. This agent incorporated the MRET probe MZF@Gd, JQ-1 (an inhibitor of PD-L1), the thermosensitive copolymer PCL-b-P(MEO2MA-co-OEGMA), and folic acid on the surface. Nanotheranostic agents killed tumor cells through magnetocaloric effects, stimulated antitumor immunity, and regulated the drug release, thereby achieving a synergistic effect between hyperthermia and immunotherapy. Moreover, MZF@Gd released from the agent sensitively detected the presence of granzyme B at the tumor site, thereby enabling an effective assessment of therapeutic efficacy. An active-targeting magnetothermally responsive nanotheranostic agent FA-P(MZF@Gd/JQ1) is developed to improve the therapeutic effect of ICI and accurately evaluate its efficacy. This agent directly killed tumor cells via magnetic hyperthermia under AMF while achieving a synergistic effect with immunotherapy. Additionally, the granzyme B levels before and after ICI therapy are detected based on the changes in the T1WI signal through MRET to accurately evaluate their efficacy.image