Tumor Microenvironment Remodeling‐Mediated Sequential Drug Delivery Potentiates Treatment Efficacy

Abstract Toll‐like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off‐target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l‐glutamic acid)‐graft‐methoxy poly(ethylene glycol)/combretastatin A4, termed CA4‐NPs) and an immunotherapy nanocarrier (apcitide peptide‐decorated poly(l‐glutamic acid)‐graft‐IMDQ‐N₃ conjugate, termed apcitide‐PLG‐IMDQ‐N₃). CA4‐NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide‐PLG‐IMDQ‐N₃ could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb‐IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of “‐N₃” to “‐NH₂” in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor‐specific CD8⁺ T cells, 4T1 and CT26 tumors with a size of ≈500 mm³ are eradicated without recurrence in mouse models.