Thermophoretic Nanomotors for Autophagic Turnover of HSP90 Potentiates Immunotherapy

ABSTRACT Therapeutic barriers and resistance limit the efficacy of immunotherapy in metastatic breast cancer. Here, we report a dual‐nanobody autophagy‐targeting chimera (AUTAC), hereafter referred to as Nb, that selectively degrades heat shock protein 90 (HSP90) via p62‐dependent autophagy, restoring tumor sensitivity to immunogenic cell death (ICD). To construct the delivery nanoplatform, Nb was preassembled into protein‐polymer nanoparticles (Nb‐PC), coated with cholesterol‐depleted 4T1 tumor cell membranes (Nb‐PC@M), and further decorated with citrate‐stabilized Pd nanoparticles (Pd NPs) to obtain Nb‐PC@MPd. This hierarchical design integrates reversible protein‐polymer assembly, biomimetic membrane coating, and asymmetric Pd anchoring. In vivo, Nb‐PC@MPd achieves EPR‐ and membrane‐assisted tumor accumulation, followed by NIR‐assisted intratumoral Nb delivery and intracellular Nb release, promotes p62‐dependent HSP90 autophagic degradation, and potentiates mild photothermal therapy (mPTT)‐induced ICD. Consequently, Nb‐PC@MPd elicits systemic antitumor immunity and effectively suppresses both tumor growth and pulmonary metastasis. This platform integrates programmable protein degradation, biomimetic thermophoretic delivery, and tumor‐directed immunomodulation, providing a versatile strategy for precision macromolecular therapeutics.