Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2.2 million new cancer cases and 1.8 million deaths annually [1]. Non-small cell lung cancer (NSCLC) is the most common epithelial lung cancer, accounting for approximately 85 % of all lung cancer types [2]. The epidermal growth factor receptor (EGFR), a transmembrane protein, serves as a receptor for members of the EGF family, triggering the EGFR signal pathway, thereby regulating cell proliferation, invasion, metastasis, apoptosis, and angiogenesis [3], [4]. Overexpression of EGFR is associated with various malignant cancers, especially advanced NSCLC [5]. Due to its significant association with NSCLC, the EGFR has been a primary target for the development of lung cancer targeted therapeutics. EGFR tyrosine kinase inhibitors (TKIs) has evolved from first to third generation. Although initially TKIs showed great therapeutic outcomes, the inevitable acquired drug resistance eventually limits their therapeutic efficacy [6], [7], [8].

Proteolysis-targeting chimera (PROTAC) has garnered significant attention as a method for targeted protein degradation. PROTAC is a bifunctional molecule consisting of an E3 ligase ligand and a protein of interest (POI) ligand, connected by a linker. PROTACs serve as a “bridge”, bringing E3 ligase and POI together, which allows the POI to be ubiquitinated and subsequently degraded by proteasome [9], [10], [11]. PROTACs are powerful tool for the targeted degradation of endogenous proteins. The first PROTAC (PROTAC 3) capable of degrading the transmembrane protein EGFR derived from the first-generation EGFR inhibitor gefitinib and was reported in 2018 [12]. In the past few years, a number of EGFR PROTACs have been developed using a similar EGFR-binding moiety [13], [14]. Although PROTACs have many advantages over small molecule inhibitors, their poor distribution in vivo and relatively low accumulation in tumors have limited their clinical application [15].

Drug delivery systems have been considered groundbreaking in achieving specific accumulation in tumor sites as well as reducing drug toxicity [15]. Therefore, drug delivery systems can be designed to facilitate the delivery of PROTACs, helping to overcome their physicochemical challenges, and ensuring their delivery to desirable target sites. Various delivery systems have been developed for the transportation of PROTACs. Gold nanoclusters were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands [16]. Carbon-dot (CD)-based PROTACs (CDTACs) were reported to degrade membrane proteins PD-L1 by conjugating PD-L1 and E3 ligase targeting probes to CDs [17]. Silica nanoparticles are particularly promising as a multifunctional delivery system due to the presence of surface silanol groups, which allow for the introduction of functional groups and the conjugation of drugs on the surface [18]. Importantly, the preparation and fabrication of silica nanoparticles are simple, scalable, cost-effective, and controllable [19]. This makes it feasible to adjust the amount of PROTACs ligands on the nanoparticles. Additionally, silica nanoparticles have demonstrated excellent biocompatibility and low toxicity, making them an ideal carrier for PROTACs to reduce the toxicity typically associated with traditional PROTACs. Their inherent stability at tumor sites further enables the recycling process of PROTACs, enhancing therapeutic efficiency. Based on these properties, silica nanoparticles were chosen as the carrier to construct a novel PROTACs delivery system. Unlike previously reported gold nanoparticles based PROTACs and carbon-dot (CD) based PROTACs [16], [17], [20], silica-based PROTACs nanoparticles were designed to integrate multiple E3 and POI ligands on the surface. This configuration allows them to simultaneously interact with multiple E3 ligases and target proteins, thus improving the protein degradation effect and addressing the associated challenges.

Here, we propose a novel silica-based EGFR-degrading nano-PROTACs for NSCLC therapy. We split the traditional PROTACs into E3 ligase ligand and EGFR ligand components, then grafted them onto the surface of silica-based nanoparticles through silanol chemistry (Fig. 1a). The silica nanoparticles bearing multiple targeting ligands were coated with liposomes to create the final SiPROTACs. SiPROTACs are expected to degrade the EGFR both in vitro and in vivo. Unlike traditional small molecule PROTACs, SiPROTACs was designed to efficiently accumulate at the tumor site, which is probably due to the enhanced permeability and retention (EPR) effect [3]. Our design is anticipated to introduce a novel nano-PROTACs capable of efficient protein degrading and effective NSCLC therapy without causing significant side effects.