Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy.

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, we describe 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-N 3 conjugate, termed apcitide-PLG-IMDQ-N 3 ). 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-N 3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ was activated selectively through the conversion of "-N 3 " to "-NH 2 " in the presence of hypoxia. The biodistribution results confirmed 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 mm 3 were eradicated without recurrence in mouse models. This article is protected by copyright. All rights reserved.