A dynamic protein corona substitution strategy for activatable imaging-guided synergistic theranostics in triple-negative breast cancer.

Antibody-drug conjugates (ADCs), exemplified by Trodelvy®, face significant limitations in triple-negative breast cancer (TNBC) therapy due to protein corona-induced targeting inefficiency and accelerated drug resistance. Herein, we present a dynamic protein corona substitution (PCS) strategy that utilizes tumor microenvironmental cues to circumvent ADC limitations while enabling phototherapy-augmented chemotherapy. Our nanoplatform, CySC, is engineered from disulfide-bridged Cy-OH and camptothecin (CPT), which can self-assemble into nanoparticles (NPs) without auxiliary molecules and undergo programmed biotransformation upon tumor accumulation. Glutathione (GSH)-triggered drug release synergizes with endogenous albumin recruitment, generating albumin-cloaked AC-Cy-OH NPs. This PCS-driven remodeling achieves real-time tumor monitoring with activated near-infrared (NIR)-I&II fluorescence, promotes tumor penetration through albumin-mediated transcytosis, and reverses CPT resistance by prolonging intratumoral drug retention. The system enables spatiotemporally precise CPT delivery, synergizing chemotherapy with photothermal-photodynamic therapy (PTT/PDT) for amplified antitumor effects. This tumor microenvironment-responsive system demonstrates superior specificity and synergistic antitumor effects in TNBC models, establishing a paradigm for protein corona reprogramming for precision oncology.