Multifunctional nanoparticles for improved immunotherapy of melanoma

. Recent advances in immune checkpoint inhibitor (ICI) based therapies have improved outcomes for many patients with advanced stage melanoma. Nonetheless, around 50% of patients do not respond to ICI therapies due to the immunologically 'cold' tumor microenvironment (TME) characterized by enriched immunosuppressive cells (e.g., regulatory T cells and tumor-associated macrophages) and cytokines that limit cytotoxic lymphocyte infiltration. Further, even for patients who respond to ICI, the response is often not durable. To address these challenges, we will develop an innovative nanotechnology approach utilizing multifunctional ultrasound- responsive nanoparticles (URNs) to enhance the outcomes of melanoma immunotherapies. URNs consist of a hydrophobically modified silica nanoparticle core and a peptide amphiphile (PA) stabilizing shell. The hydrophobic cores stabilize surface gas pockets, enabling strong cavitation activity under FUS treatment, thereby mechanically disrupting the tumor tissue and releasing immunostimulatory tumor antigens and danger- associated molecular patterns (DAMPs). In addition, we showed that intratumorally injected URNs significantly improved the tumor retention and cellular internalization of drugs conjugated to their PA shells through physical interactions of PAs with hydrophobic URN surfaces and cell membranes. In this proposal, we will leverage the multifunctionality of URNs by combining mechanical tumor ablation with sustained delivery of a Toll-like receptor 7/8 (TLR7/8) agonist, which can generate pro-inflammatory, anti-cancer responses. Accordingly, our central hypothesis is that the release of tumor antigens and DAMPs through ablation, combined with a durable pro- inflammatory tumor microenvironment driven by sustained TLR7/8 activation, will synergistically stimulate innate and adaptive immune responses capable of achieving curative outcomes. To achieve this overall goal, in the first Aim, we will optimize the FUS ablation conditions to maximize the innate and adaptive immune responses generated by URN-enabled tumor ablation. In the second Aim, we will test a rationally designed library of URNs with different hydrophobic modifications and PA coatings to optimize the sustained delivery of intratumorally injected TLR7/8 agonists, aiming to achieve and retain a pro-inflammatory TME without causing toxicity. Finally, we will combine URN-enabled ablation with TLR7/8 agonist delivery and evaluate its efficacy in multiple clinically relevant mouse melanoma models, including a spontaneous model. In summary, we propose developing a multifunctional nanomaterial platform for enhanced immunotherapy of melanoma. In addition, the approach described here may be used to deliver other adjuvant immunotherapies or applied to many other cancers, such as breast, prostate, and liver cancers, lending it broad utility across various cancer types. Project Number: 1R01CA311580-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Adem Yildirim | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $640,113 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11340962