Background: A high unmet medical need exists for new therapies in NMIBC to reduce common risks of recurrence, progression and, ultimately, cystectomy. Belzupacap sarotalocan, a novel investigational virus-like drug conjugate (VDC), has a dual mechanism of action designed to provide 1) selective binding to malignant cells, causing acute necrosis upon light activation, and 2) long-term anti-tumor immunity as demonstrated in pre-clinical models. This Phase 1 trial is designed to evaluate the feasibility and safety of intramural injection with or without intratumoral injection of belzupacap sarotalocan for treatment of NMIBC. The hypothesis is that after near infrared light activation, targeted distribution of belzupacap sarotalocan at high concentrations at the tumor base could necrose the tumor where it is most likely to be invasive. In turn, the tumor targeted pro-immunogenic cell death could potentially lead to an anti-tumor immune response preventing the risk for recurrence, progression and metastasis. Methods: This is an actively enrolling “window of opportunity” trial (NCT05483868) in low, medium or high risk NMIBC subjects scheduled to undergo TURBT or cystectomy per standard of care. A pre-treatment biopsy will be performed in up to 23 adult subjects enrolled in 4 cohorts, who will be given belzupacap sarotalocan +/- laser as shown in the table. The primary endpoint is incidence and severity of treatment-related adverse events, serious adverse events regardless of attribution, and incidence of dose-limiting toxicities. Each cohort will have a safety review for the injection procedure and laser (as needed), after 3 subjects have been treated and followed for 28 days. Secondary endpoints are based on histopathology and include assessment of local biodistribution of belzupacap sarotalocan measured via immunohistochemical staining, tumor necrosis, and evidence of an immune response via comparison of pre-treatment biopsy to TURBT/cystectomy samples after treatment. Statistical analysis plan includes descriptive statistics for the above endpoints. Clinical trial information: NCT05483868.