The goal of this project is to conduct a Phase I clinical trial to determine the recommended Phase II dose (RP2D) of bladder cancer-targeting micelles loaded with a chemotherapeutic drug paclitaxel (PTX). With a VA Career Development Award-2 and VA Merit grant (PI: Pan), we developed a bladder cancer-specific targeting ligand named PLZ4, and a PLZ4-coated PTX-loaded nanoscale micelle (PPM) platform that can specifically deliver the drug load into bladder cancer cells both in vitro and in vivo. This proposed clinical trial is to conduct a first-in-human trial to use PPM for the treatment of non-myoinvasive bladder cancer (NMIBC). Bladder cancer is one of the ten most common cancers in the United States. NMIBC accounts for around 75% of bladder cancer cases at diagnosis. The current first-line treatment approach of transurethral resection followed by intravesical instillation of therapeutic agents, usually Bacillus Calmette-Guérin (BCG), is associated with a recurrence rate of around 70% at two years. Pembrolizumab and valrubicin are the only second-line drug approved by the Food and Drug Administration (FDA) with a response rate of 40% and 20-40%, respectively. Considering that bladder cancer is among the top ten most common cancers and over 70% of bladder cancers are diagnosed as NMIBC, there are huge unmet medical needs for developing more effective therapies. This primary objective of the proposed Phase I trial is to determine the recommended Phase II dose (RP2D) of PPM. The secondary objectives are to assess the toxicity, obtain preliminary efficacy information of PPM, and determine systemic absorption after intravesical instillation of PPM. Up to 25 patients with recurrent or refractory NMIBC after a standard first-line intravesical therapy pembrolizumab treatment will be recruited. PPM will be given as intravesical instillation once weekly for six weeks. The toxicity will be assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The efficacy will be determined by urine cytology and cystoscopy two weeks after finishing treatment. Molecular correlative studies will be performed.