Fibrin-targeted and pH-responsive liposomes for synergistic thrombolysis and thrombotic microenvironment reprogramming

Abstract

Thrombolytic therapy, exemplified by tissue plasminogen activator, is often constrained by a short half-life, non-specific action, and bleeding risks. To address these limitations, we developed tLipo@UA, a fibrin-targeted and pH-responsive liposomal system for the co-delivery of urokinase-type plasminogen activator (uPA) and aspirin (acetylsalicylic acid, ASA). This system was functionalized with the CREKA peptide for specific thrombus homing and incorporated cholesteryl hemisuccinate (CHEMS) to confer pH-sensitive drug release within the acidic thrombotic microenvironment.Experiments conducted both in vitro and in vivo demonstrated that tLipo@UA achieved efficient thrombus targeting and responsive drug release. The released uPA effectively dissolved thrombi, while the co-delivered ASA modulated the thrombus microenvironment by suppressing inflammatory cytokine release, thereby exhibiting a synergistic thrombolytic and anti-inflammatory effect. The encapsulation significantly prolonged the circulation time of uPA and enhanced its localized efficacy. Furthermore, the system showed a favorable biosafety profile. Collectively, tLipo@UA presents a promising strategy for enhancing thrombolytic potency and achieving microenvironment reprogramming with reduced off-target risks, offering a rational design for dual-function drug carriers in the treatment of thrombotic diseases.