Cutaneous squamous cell carcinomas (cSCC) are responsible for more than twice the number of skin cancer deaths than melanoma, representing up to 50% of all skin cancers. Approximately 700,000 cases are diagnosed annually in the United States, but Veterans have a higher risk for cSCC because of age and extensive exposures during the line of duty to UV radiation and arsenic-based chemical warfare agents. Most cSCC can be successfully treated by surgical excision or Mohs Micrographic Surgery (Mohs); however, a subset of cSCC cases result in locoregional recurrence, metastases, and death. The poor prognoses for many Veterans with cSCC result in a substantial unmet need for better treatment options, especially for those who request a non-surgical treatment option or who are not a candidate for surgery because they are immunosuppressed or have other comorbidities. The novel technology in this proposal, Laser-Activated NanoTherapy (LANT), can meet this unmet need for an alternative to radiation when surgery is not an option. LANT is a thermal ablation platform therapy using near-infrared laser excitation of gold nanorods (AuNRs) that generates enough heat to induce site-specific cellular death. The innovation of our technology is the nanoparticle design and the resulting therapeutic outcomes. In our preliminary studies, LANT demonstrated (a) 100% SCC cell death at the highest concentration on our dose-escalation curve in vitro, and (b) complete tumor regression after one treatment iteration with clear tumor margins in subcutaneously-xenografted squamous cell carcinoma in mice, compared to three control groups, no-treatment, laser-only, and AuNRs- only. Based on these findings, we propose a study designed to demonstrate that LANT is safe and translate LANT from bench to bedside with three aims. For Aim 1, we will demonstrate the biodistribution, clearance, and safety of AuNRs in a murine tumor model and a domestic swine model to acquire PK/PD data using ICP- MS, hematology/serology, and histology. We will verify the distribution of AuNRs, heat generation, and LANT- induced injury to the tumor, tumor margins, and surrounding tissues using 3D ultrasound imaging, K-type thermocouples, and IR thermographic cameras. We will also validate LANT safety at different laser output powers by capturing gross appearance changes with photographic imaging and analyzing morphological changes with histological evaluation of tumors, tumor margins, and surrounding tissues. We will work with our FDA consultant and seven (7) clinical partners to obtain FDA and IRB approvals before beginning the pilot study. For Aim 2, we will recruit Veterans (n = 10) who have biopsy-confirmed local, low-risk cSCC. Veterans will receive 3-D ultrasound-guided injections of AuNRs during LANT. Veterans will also receive the standard of care Mohs Micrographic Surgery to confirm clear tumor margins 21 days after LANT. We will employ an adaptive Bayesian Continual Reassessment Method (CRM) to deter...