High-grade gliomas (HGGs; WHO grades III and IV) encompass a heterogeneous group of malignant brain tumors characterized by aggressive behavior and dismal prognosis. The primary subtypes include anaplastic astrocytoma (grade III), with a global incidence of approximately 0.5 per 100,000 persons per year, and glioblastoma multiforme (GBM, grade IV), which is the most common and lethal form, accounting for 54–73 % of diffuse gliomas [1], [2]. Globally, the incidence of diffuse gliomas in adults varies, with age-adjusted rates ranging from 1.9 per 100,000 in East Asia to 9.6 per 100,000 in Australia/New Zealand, while Western Europe and North America show intermediate rates (∼7.8–8.5 per 100,000) [2]. In the United States, HGGs represent nearly 85 % of malignant gliomas, with GBM incidence reaching 3.2–4.2 per 100,000 annually. HGG’s are more incident in caucasian males, and incidence rises with age, peaking between 75 and 84 years old [3], [4].

The treatment of HGG’s remains one of the greatest challenges in neuro-oncology. Current standard-of-care consists of maximal safe surgical resection, followed by radiotherapy and adjuvant chemotherapy with temozolomide (TMZ), an oral alkylating agent. While surgical resection is essential to reduce tumor burden, complete tumor excision is rarely achievable due to the highly infiltrative nature of HGGs and their localization in eloquent brain regions. Postoperative radiotherapy combined with adjuvant TMZ, known has modestly improved survival; median overall survival for GBM remains between 12 and 15 months, and recurrence is highly frequent, typically occurring within 6–9 months of initial treatment [5], [6].

One of the major challenges in treating HGG’s lies in their molecular heterogeneity and the expression of markers associated with aggressiveness and therapeutic resistance. Among these, CD44, a transmembrane glycoprotein and major receptor for hyaluronic acid (HA), stands out as a critical challenge. CD44 is frequently overexpressed in HGGs, especially in GBM, and its increased expression is strongly correlated with poor prognosis, enhanced invasiveness, and a mesenchymal-like phenotype. This phenotype is characterized by high cellular motility, strong invasive potential, and intrinsic resistance to both radio- and chemotherapy. Additionally, evidence suggest CD44 contributes to the maintenance of glioma stem-like cells, supporting tumor self-renewal, and has been linked to increased immune evasion and tumor recurrence [7].

Researchers have been focusing on different strategies to improve the therapy of brain tumors. In this context, numerous compounds—especially natural polyphenols, terpenoids, and alkaloids—have demonstrated promising antitumor activity in in vitro and in vivo preclinical models. However, their clinical translation has been hampered by unfavorable physicochemical characteristics, such as poor aqueous solubility, limited stability, low oral bioavailability, and restricted ability to cross the BBB, which compromise brain delivery and therapeutic efficacy for CNS tumors [8], [9], [10].

Resveratrol (RSV) is a natural polyphenolic compound found in grapes, red wine, peanuts, and soy. It is known for its antifungal, antiviral, anti-inflammatory, antioxidant, and anti-aging properties. Additionally, RSV exhibits antitumor activity [11]. It works by suppressing oncogenes or activating tumor suppressor genes, leading to cell cycle arrest, induction of apoptotic pathways, and inhibition of metastasis [12], [13]. RSV influences all three stages of carcinogenesis—initiation, promotion, and progression—by interacting with molecular targets such as P53, caspases, P21, and the PI3K/AKT pathway. These interactions affect apoptosis, the cell cycle, protein kinases, metastasis, and cellular invasion [14], [15]. Additionally, RSV improves the tumor response to radio- and chemotherapy, as demonstrated in cases where temozolomide (TMZ) was combined with RSV inducing apoptosis in GBM stem cells through DNA double-strand breaks. RSV can also downregulate the expression of MGMT, a repair enzyme that causes resistance to TMZ, potentially overcoming resistant cells [16]. However, despite its ability to cross the BBB certain properties of RSV, such as low bioavailability, poor water solubility, high photosensitivity, and low oxidative stability, limit its clinical application [17].

Over the last decades, nanotechnology has emerged as a promising tool to overcome the delivery challenges of bioactive compounds with unfavorable properties, especially for CNS applications. In particular, the use of nanoparticles has demonstrated great potential to repurpose existing shelf therapeutics for the treatment of brain tumors [18]. Among several types of nanoparticles, nanostructured lipid carriers (NLCs), composed of mixtures of solid and liquid lipids stabilized by surfactants, offer notable advantages, including biocompatibility, enhanced drug loading, controlled release, and the possibility of surface functionalization. The surfaces of these lipid-based nanoparticles can be modified with different targeting ligands (i.e.: proteins, aptamers, polysaccharides and other polymers) which bind specific elements present in the tumor microenvironment or the neoplastic cells, improving delivery efficiency and specificity [19], [20].

Herein, we describe the development of CD44-targeted NLCs encapsulating trans-resveratrol, using surface-coating with HA as the targeting strategy. We hypothesize that HA-functionalized NLC-RSVs will (i) improve RSV solubility and stability; (ii) improve preferential delivery to CD44-expressing glioma cells; and (iii) enhance cytotoxic effects compared to non-targeted or free RSV. We determined their physicochemical properties, in vitro cellular uptake, and cytotoxic efficacy against high-grade glioma (C6) cells as a proof-of-concept.