Recent advances in nanomedicine have led to the introduction and subsequent establishment of nanoparticles in cancer treatment and diagnosis. Nonetheless, their application is still hindered by a series of challenges related to their biocompatibility and biodistribution. In this paper, we take inspiration from the recently produced and widely spread COVID vaccines, based on the combinational use of ionizable solid lipid nanoparticles, cholesterol, PEGylated lipids, and neutral lipids able to incorporate mRNA fragments. Here, we focus on the implementation of a lipidic formulation meant to be used as a smart coating of solid-state nanoparticles. The composition of this formulation is finely tuned to ensure efficient and stable shielding of the cargo. The resulting shell is a highly customized tool that enables the possibility of further functionalizations with targeting agents, peptides, antibodies, and fluorescent moieties for future in vitro and in vivo tests and validations. Finally, as a proof of concept, zinc oxide nanoparticles doped with iron and successively coated with this lipidic formulation are tested in a pancreatic cancer cell line, BxPC-3. The results show an astonishing increase in cell viability with respect to the same uncoated nanoparticles. The preliminary results presented here pave the way towards many different therapeutic approaches based on the massive presence of highly biostable and well-tolerated nanoparticles in tumor tissues, such as sonodynamic therapy, photodynamic therapy, hyperthermia, and diagnosis by means of magnetic resonance imaging.

New treatment strategies are urgently needed for pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest tumors nowadays. PDAC is marked by hypoxia, intrinsic chemoresistance, a "cold" tumor microenvironment, and dense desmoplastic stroma, which hinders drug penetration. This study investigates the combined effect of iron-doped, lipid-coated zinc oxide nanoparticles enhanced with a fluorescent sonosensitizer and local ultrasound stimulation in treating PDAC. Nanoparticles were synthesized and coated by lipids, and their physiochemical properties were characterized by assessing reproducibility, stability, and efficient inclusion of the sonosensitizer. In vitro, sonosensitizer-enhanced nanoconstructs were tested on a KPC murine PDAC cell line in combination with ultrasound to evaluate their cytotoxicity and assess their efficacy. In vivo, NPs were further coupled with AlexaFluor 700 to allow their localization over time, and the nanoconstructs were intratumorally administered to a subcutaneous murine PDAC model to enhance local bioavailability and tumor visualization and minimize off-target effects of systemic delivery. Biodistribution, efficacy, flow cytometry, and survival studies were carried out on different cohorts of mice. The sonosensitizer-enhanced nanoconstructs, combined with ultrasound, triggered significant reactive oxygen species (ROS) production, reducing the KPC cell viability. In vivo, the antitumor efficacy was particularly pronounced with ultrasound stimulation, demonstrating a synergistic interaction between the nanoparticles and ultrasound. Moreover, increased immune cell infiltration, enhanced cancer cell apoptosis, and prolonged survival of the treated animals were achieved. These findings highlight the potential of a synergistic therapeutic approach combining lipid-coated sonosensitizer-loaded nanoparticles and ultrasound stimulation as an effective therapy for PDAC and in situ monitoring.

Recent advances in nanomedicine toward cancer treatment have considered exploiting liposomes and extracellular vesicles as effective cargos to deliver therapeutic agents to tumor cells. Meanwhile, solid-state nanoparticles are continuing to attract interest for their great medical potential thanks to their countless properties and possible applications. However, possible drawbacks arising from the use of nanoparticles in nanomedicine, such as the nonspecific uptake of these materials in healthy organs, their aggregation in biological environments and their possible immunogenicity, must be taken into account. Considering these limitations and the intrinsic capability of phospholipidic bilayers to act as a biocompatible shield, their exploitation for effectively encasing solid-state nanoparticles seems a promising strategy to broaden the frontiers of cancer nanomedicine, also providing the possibility to engineer the lipid bilayers to further enhance the therapeutic potential of such nanotools. This work aims to give a comprehensive overview of the latest developments in the use of artificial liposomes and naturally derived extracellular vesicles for the coating of solid-state nanoparticles for cancer treatment, starting from in vitro works until the up-to-date advances and current limitations of these nanopharmaceutics in clinical applications, passing through in vivo and 3D cultures studies.

The implementation of drug delivery systems in nanomedicine aims to improve the efficacy, safety and stability of therapeutic substances within the body, while controlling their rate and time of release. While numerous reviews over the years have thoroughly summarized the most recent advances and applications of drug delivery systems, to the best of our knowledge none has ever approached the topic by focusing on the impact of their structural order on both drug loading and the resulting therapeutic outcome. In this review, we aim to highlight the importance of considering the intrinsic properties of the carriers in terms of atomic, molecular and supramolecular order. Indeed, each level of order enables specific interactions between the carrier and cargo, leading to unique properties of the resulting nanosystems. Depending on the final application, the choice of a specific drug delivery system can therefore significantly influence the therapeutic effects. Thus, our work aims to facilitate the design of drug delivery systems by elucidating which level of intrinsic material order is most appropriate for a given clinical challenge. The literature search included PubMed and Scopus covering the period from January 2000 to July 2025.

The development of safer, more effective, and tumor-specific therapeutic strategies remains a major challenge in oncology. Conventional treatments such as chemotherapy and radiotherapy often cause severe side effects and are limited in their ability to target deep-seated or resistant tumors. In this context, sonodynamic therapy (SDT) has emerged as a promising, non-invasive option, harnessing low-intensity ultrasound to activate sonosensitizers deep within tissues and generate cytotoxic reactive oxygen species (ROS) that selectively induce cancer cell death. Interestingly, SDT can also be combined with other therapies to achieve synergistic effects. However, despite encouraging preclinical results, SDT clinical translation is hindered by the poor aqueous solubility, instability, and low tumor specificity of traditional sonosensitizers. To overcome these limitations, recent studies have focused on employing extracellular vesicles (EVs), especially exosomes, as natural, biomimetic nanocarriers for sonosensitizer delivery. EVs offer unique advantages, including high biocompatibility, low immunogenicity, and intrinsic tumor-targeting ability, which make them ideal platforms for improving the therapeutic precision of SDT. Although several delivery strategies have been proposed, a comprehensive and focused overview of approaches specifically designed to enhance SDT performance using EVs is currently lacking. This review summarizes recent advances in integrating EVs with SDT for cancer treatment. It discusses the mechanisms underlying SDT, the engineering strategies developed to enhance exosome functionality, and the synergistic effects achieved through this combination. Furthermore, this review emphasizes that EV-based SDT not only enhances tumor accumulation of the therapeutic nanoplatforms, but also actively remodels the tumor microenvironment by improving oxygen availability, reversing immunosuppressive conditions, and triggering durable antitumor responses. Finally, the review addresses the translational challenges and outlines the critical future directions required to advance this promising therapeutic approach toward clinical application.