pH-Responsive hyaluronic acid-based nanoplatform for prolonged intraocular retention and synergistic chemotherapy of retinoblastoma

Intravitreal chemotherapy is a widely employed therapeutic strategy for retinoblastoma. However, its clinical efficacy and safety are considerably compromised by rapid drug clearance from the vitreous cavity and off-target toxicity. To address these limitations, we developed a pH-responsive, hyaluronic acid-based dual drug-loaded nanoplatform (HDLNs) for intravitreal co-delivery of doxorubicin and lapatinib. The nanoscale dimensions and negative surface charge of HDLNs facilitate efficient diffusion within the vitreous gel network while enhancing cellular uptake by Y79 cells. Upon exposure to the acidic intracellular microenvironment, HDLNs rapidly disassemble and trigger the synchronized release of both payloads, thereby synergistically inhibiting tumor cell proliferation and migration. In vivo investigations demonstrated that intravitreal administration of HDLNs significantly prolonged intraocular drug retention and effectively suppressed tumor progression in an intraocular Y79 retinoblastoma mouse model. Importantly, HDLNs substantially mitigated ocular and systemic toxicities associated with intravitreal chemotherapy, exhibiting a favorable in vivo safety profile. Collectively, this tailored drug delivery nanoplatform represents a promising and feasible strategy for safe and effective intravitreal chemotherapy against retinoblastoma.