Over the years, nanomedicines have gained growing interest for their ability to customize release profiles, diminish side effects and safeguard the drugs and therapeutics against degradation [1], [2], [3], [4], [5]. Among various types of nanoparticles such as drug-laden polymer or lipid nanoparticles, liposomes, polymer-drug conjugates, polymersomes, carbon nanotubes and gold nanoparticles, lipid- and polymeric-based nanoparticles stand out as two extensively studied and promising classes of drug delivery systems [6]. Both techniques have outstanding biocompatibility and biodegradability [7], lipid nanoparticles (L-NPs) have the capacity to encapsulate and transport both hydrophobic and hydrophilic drugs effectively [8], facile preparation through methods that are free from organic solvents, and straightforward scalability [9], [10], [11]. On the other hand, polymeric nanoparticles (P-NPs) offer their own set of advantages that they are easily fabricated, non-toxic, non-immunogenic, and have a wide diversity in structure and functionality, allowing for easier and more efficient functionalization for targeted drug delivery [12], [13], [14], [15]. Despite notable advancements in designing nanoparticle carrier systems with enhanced functionality, specificity, and disease-targeting capabilities, only a handful of drugs based on lipids/protein have reached the market, e.g., Doxil®, AmBisome®, Amphotech®, Epaxel®, Abraxane®, Onpattro®, and certain Covid-19 vaccines. While there could be multiple explanations; limited market presence in parts could be attributed to the choice of drug and the corresponding disease. The type of target, route of administration, limited efficacy of active systems due to lack of functionality compared to passive systems, poorly established risk–benefit profiles, economic viability, and generalizing based on size without considering the carrier material and drug [16], [17]. In line with lipids, conventional polymers are also limited by their functionality, drug payload, and choice of ligands [18], [19], [20].

Very recently, there has been a significant drive-in excipients research to meet the challenges posed by the new drug discovery pipeline [21], [22]. In this context, hybrid nanoparticles like (a) polymers physically adsorbed on the surface of L-NPs, (b) polymers trapping lipid vesicles, (c) polymers covalently bonded to the polar head of phospholipid and (d) amphiphilic polymers homogenously distributed with L-NPs monomers forming a network around lipid vesicles are finding applications in drug delivery [23], [24], [25], [26], [27]. However, these hybrid particle architectures still need to be more adequately reported, demanding a more profound comprehension of their preparation methods, physicochemical properties, and biological behavior.

Here, we report a novel hybrid nanoparticle (H-NPs), constituted of a core made up of glyceryl tristearate, a triglyceride, while the surface is comprised of a polymer functionalized with gambogic acid (P2s-GA). The polymer (P2s-GA) promotes transferrin receptor interaction, facilitating transcytosis across the intestinal barriers upon oral administration [28], [29], [30], [31]. The H-NPs combine the advantages of both L-NPs and P-NPs, enabling the development of oral drug products [32]. To demonstrate the feasibility of H-NPs as a delivery vehicle, we have used Urolithin A (UA) as a model compound. UA is a naturally occurring gut metabolite of ellagic acid known for its intriguing anti-inflammatory and antioxidant properties. It enhances cellular health by promoting mitophagy and mitochondrial function while mitigating harmful inflammation [33]. However, its clinical application is hindered by its poor oral bioavailability [32], [33], [34], [35]. We have conducted an in vitro efficacy study in cisplatin-induced injury in healthy human proximal tubular cells (HK2), where H-NPs offered superior anti-inflammatory properties compared to individual NPs. Further studies in whole body systems, e.g., cancer models, are needed to validate the use of H-NPs in preventing chemotherapy-induced kidney injury without compromising the chemotherapeutic efficacy.