As the leading primary intraocular malignancy in adults, uveal melanoma (UM) affects 5 to 10 individuals per million. The liver and lungs are the most frequent sites of distant metastasis, with an incidence rate approaching 90 % (Jager et al., 2020, Diener-West et al., 2005). Researches showed that vitreous injections produced higher local drug concentrations at the site of UM, making it one of the most effective treatments (Chen et al., 2023, Yang et al., 2022). However, this invasive route of administration is uncomfortable to patients and may cause side effects, including intraocular hemorrhage and retinal detachment (Baumal et al., 2020, Jonas et al., 2005, Brown et al., 2021). Therefore, the minimally invasive approach to drug delivery has become an ideal option for treating UM (Li et al., 2020, Chang et al., 2024). Compared to vitreous injection, topical instillation and systemic administration offer safer alternatives. However, the low bioavailability of eye drops limits their effectiveness (You et al., 2019, Gupta et al., 2012 Rotchford and Murphy, 1998); and the inevitable systemic toxicity and complex tumor microenvironment (TME) hinder the therapeutic effects of systemic treatments (Brassart-Pasco et al., 2020, Khawar et al., 2015, Li et al., 2020, Li and Burgess, 2020, Mantovani et al., 2008). Consequently, an active targeted drug delivery platform was developed to precisely direct drug accumulation at the tumor site while reducing adverse effects for uveal melanoma.

LDL is structured as a core–shell complex, where cholesteryl esters and polyunsaturated fatty acids form the core, and the surrounding shell consists of phospholipids, cholesterol, and apolipoprotein B-100 (ApoB-100). It has advantages such as biocompatibility, biodegradability, and efficient drug delivery (Zhu and Xia, 2017). Unlike traditional biomimetic systems that primarily rely on passive targeting through the Enhanced Permeability and Retention (EPR) effect, such as red blood cell membrane-coated nanoparticles and platelet membrane-based carriers, LD-DPVP nanoparticles uniquely combine both active and passive targeting mechanisms. LDL can interact with LDL receptors (LDLR) via its external ApoB-100, a protein that is overexpressed in proliferating cells, particularly in cancerous ones (Di and Maiseyeu, 2021). However, the scarcity of natural LDL and the complexity of the extraction process present significant challenges (Dihazi et al., 2008). Based on biomimetic strategies, recombinant LDL (rLDL), which mimics the biological composition and structure of natural LDL, providing a new strategy for targeted tumor therapy.

Photodynamic therapy (PDT), recognized for its non-invasive nature, has been increasingly applied in clinical practice in recent years (Agostinis et al., 2011, Bakri and Kaiser, 2004). It utilizes photosensitizers (Ps) with high spatiotemporal selectivity and low drug resistance to generate reactive oxygen species (ROS) to treat malignant tumors (Agostinis et al., 2011). Additionally, the transparent vitreous humor allows effective light penetration, providing significant potential for PDT in treating ocular diseases (Cerman and Çekiç, 2015, Ruan et al., 2022). Exposure to specific wavelengths of laser light activates the Ps, causing a shift from the ground to the excited state. Upon relaxation, they release energy to oxygen molecules, forming singlet oxygen (1O2), which kills tumor cells. For instance, verteporfin (VP) can efficiently generate 1O2 and superoxide anions under 690 nm light, exhibiting superb phototoxicity (Bakri and Kaiser, 2004, Huang et al., 2020). However, the abnormal TME, especially immature and leaky blood vessels, which can hinder drug penetration and accumulation, thereby limiting the effectiveness of PDT in treating UM (Muz et al., 2015).

Dexamethasone (DEX) is a widely used potent glucocorticoid, typically employed to control side effects associated with chemotherapy, radiotherapy, and immunotherapy (Zhang et al., 2019, Bala et al., 2013). Recent studies have shown that DEX can normalize the tumors vascular morphology and enhance blood perfusion in tumor tissues by modulating the TME (Chauhan et al., 2020), thereby facilitating targeted drug delivery and accelerated release of nanoparticles. However, high doses and prolonged use of DEX can lead to steroid-induced side effects due to the expression of glucocorticoid receptors in most cell types (Yu et al.,2021). The prodrug strategy allows for the on-demand release of active drugs at specific sites (Wang et al., 2023); thus, a ROS-responsive dexamethasone prodrug (referred to as DPD) was synthesized, characterized by a thioester bond. By locally irradiating with red or near-infrared light, exogenous ROS generated by Ps can cleave the ROS-sensitive thioether bond, facilitating drug release at the tumor site and achieving a cascading reaction (Xu et al., 2017, Ding et al., 2021 Feb 25, Meng et al., 2021).

Herein, a novel biomimetic nanoparticle system (LD-DPVP NPs) based on rLDL for the co-delivery of the hydrophobic drugs VP and DPD was proposed, achieving a synergistic antitumor effect through complementary effect of PDT and DEX. As shown in Scheme 1, ApoB-100 specifically targeted LDLR on tumor surface after intravenous injection, actively guiding the nanoparticles to the tumor site. Once internalized by tumor cells, LD-DPVP NPs were stimulated to release explosive drugs under NIR irradiation, generating abundant ROS, which promoted tumor cell apoptosis and triggers DEX circulation. The simultaneously released DEX could normalize the TME, enhancing the penetration and accumulation of nanoparticles. Overall, the recombinant LDL biomimetic nanoparticle system was designed to effectively deliver hydrophobic drugs to ocular tumors, aiding in TME normalization and improving the therapeutic efficacy against UM.