Rationally designed NIR-II excitable and endoplasmic reticulum-targeted molecular phototheranostics for imaging-guided enhanced photoimmunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by an extremely poor prognosis. Photoimmunotherapy has emerged as a promising strategy for the treatment of TNBC. This approach works by selectively destroying tumor cells, releasing tumor-associated antigens, activating the immune system, and effectively inhibiting tumor proliferation and metastasis. However, the majority of current phototheranostic approaches are hindered by limited tissue penetration in the first near-infrared (NIR-I) and ultraviolet-visible (UV-Vis) regions. Additionally, due to the lack of specific subcellular targets, it may be difficult to effectively treat deep-seated lesions with ambiguous and extensive boundaries caused by TNBC metastases. Consequently, the development of effective, deep-penetrating, organelle-targeted phototheranostics is essential for enhancing treatment outcomes in TNBC. This work proposes a novel molecular design strategy of NIR-II phototheranostics to realize planar rigid conjugation and alkyl chain functionalization. The di-hexaalkyl chains in a vertical configuration on the donor (4H-cyclopenta[2,1-b:3,4-b'] dithiophene) and shielding units (fluorene) are introduced to construct a S-D-A-D-S type NIR-II phototheranostics (IR-FCD). The planar and rigid structure of IR-FCD exhibits a robust intramolecular charge transfer capability, a lower band gap, enhanced photon absorption properties, and significant steric hindrance from vertically arranged alkyl chains to minimize non-radiative energy loss. By incorporating N-(but-3-yn-1-yl)-4-methylbenzenesulfonamide at the terminus of an elongated alkyl chain, followed by self-assembly into DSPE-S-S-PEG2000, NIR-II excitable phototheranostics (IR-FCD-Ts NPs) with endoplasmic reticulum (ER) targeting capability were successfully synthesized for imaging-guided photoimmunotherapy of TNBC. The IR-FCD-Ts NPs demonstrate exceptional optical characteristics, with maximum absorption at 1068 nm (extending to 1300 nm) and emission at 1273 nm (extending to 1700 nm), along with a high molar absorption coefficient of 2.76*10⁴ L/mol·c at 1064 nm in aqueous solution. Under exposure to 1064 nm laser irradiation, IR-FCD-Ts NPs exhibit superior photothermal properties and have the potential for photodynamic therapy. By targeting ER, thereby inducing ER stress and significantly enhancing immunogenic cell death (ICD) in tumor cells, it triggers a strong antitumor immune response and inhibits the proliferation and metastasis of TNBC.