Biomimetic Composite Nanoparticles with Immune Modulation and CRISPR Gene Editing for Enhancing Mild Photothermal Therapy-Based Synergistic Antitumor Therapy

Photothermal therapy (PTT) is a promising cancer treatment. However, the high temperature generated during therapy may harm normal tissues, and the immunosuppressive microenvironment induced by tumor-associated macrophages (TAMs) hinders immune clearance of residual tumors after PTT. Therefore, developing mild PTT and remodeling the immunosuppressive microenvironment are crucial to improve antitumor efficacy and irradiation safety. Herein, we developed a biomimetic composite nanoparticle based on ribonucleoprotein (RNP), tetra-methylphenidine (TMP195), and a designed amphiphilic NIR-II conjugated polymer, PCQ–PEG-NH 2 . PCQ–PEG-NH 2 exhibits a high photothermal conversion efficiency (58.1%), enabling PTT under safe laser intensity. The loaded RNP specifically knocks down the HSP90α gene, reducing tumor thermotolerance to enhance mild PTT efficiency. TMP195 reprograms TAMs from M2 to M1 phenotype, alleviating immunosuppression. Additionally, macrophage membrane modification endows nanoparticles with excellent biocompatibility and active tumor-targeting ability. In a breast cancer mouse model, this synergistic strategy outperformed traditional PTT, providing a promising strategy for mild-PTT tumor therapy with high efficacy.