Photothermal Reprogramming of In Vivo Protein Corona on Nanoparticles for Enhanced Breast Cancer Nanotherapy

Nanomedicines hold great promise for breast cancer theranostics; however, their therapeutic efficacy is frequently compromised by spontaneous protein corona formation in complex physiological environments. Herein, we develop a photothermal strategy for in vivo protein corona reprogramming to enhance nanoparticle (NP) accumulation and anticancer efficacy. This strategy utilizes theranostic BBT (4,7-bis(4-(2-ethylhexyl)thiophen-2-yl)benzobis[c][1,2,5]thiadiazole) NPs featuring superior photothermal conversion, stacking-induced charge transfer-enhanced Raman scattering (SICTERS), and photoacoustic imaging capabilities, enabling localized photothermal heating for controlled protein corona regulation and real-time efficacy monitoring. In orthotopic breast cancer models, we demonstrated that localized photothermal heating dynamically reprogrammed protein corona composition in an irradiation time-dependent manner, resulting in significant enrichment of dysopsonins (e.g., albumin and apolipoprotein A-I) on BBT NPs. This compositional remodeling effectively shielded BBT NPs from the mononuclear phagocyte system surveillance. Real-time Raman and photoacoustic imaging revealed that photothermally regulated BBT NPs exhibited a significantly prolonged circulation half-life (from 19.3 to 48.4 h), reduced hepatic sequestration, and enhanced tumor accumulation relative to untreated controls. Consequently, this in vivo protein corona reprogramming strategy notably improved the photothermal antitumor efficacy of BBT NPs. This work establishes photothermal regulation as a promising modality for optimizing NP delivery efficiency, with broad implications for enhancing nanomedicine-based cancer therapy.