Self-assembly of paclitaxel derivative and fructose as a potent inducer of immunogenic cell death to enhance cancer immunotherapy

Immunotherapy shows promise for tumor control but is limited by low response rates. Paclitaxel (PTX) induces immunogenic cell death (ICD), yet conventional delivery systems face challenges like low drug loading and insufficient intracellular accumulation, reducing ICD efficacy. Small-molecule self-assembled PTX nanoparticles offer a promising solution due to high drug loading and dose delivery. In this study, PTX was conjugated with phenylboronic acid (PBA) to form the derivative PTX-PBA, which spontaneously self-assembled with fructose into nanoparticles (PTX-PBA-Fru NPs). These nanoparticles exhibited a uniform size of 107.8 ± 2.9 nm, a PDI of 0.064 ± 0.042, and a zeta potential of -12.2 ± 0.9 mV, with spherical morphology. In 4T1 tumor-bearing mice, PTX-PBA-Fru NPs significantly enhanced tumor inhibition (p < 0.001) and increased body weight (p < 0.05). No allergic reactions in healthy Balb/c mice and the maximum tolerated intravenous dose reached 200 mg/kg, underscoring its favorable safety profile of PTX-PBA-Fru NPs. The ICD effects induced by PTX-PBA-Fru NPs, when combined with the immunomodulator resiquimod (R848), elicited a robust anti-tumor immune response. This combination therapy effectively remodeled the immunosuppressive tumor microenvironment and achieved a 37.5 % tumor eradication rate. Moreover, it established long-term immune memory, providing protection against tumor re-challenge. This novel PTX formulation demonstrates strong anti-tumor effects, safety, and clinical potential in combination with R848-based immunotherapy.