NLS-functionalized semiconducting polymer nanoparticles for enhanced intracellular accumulation and combined photodynamic-photothermal cancer therapy.

Traditional cancer treatments, including surgery, radiotherapy, and chemotherapy, are often limited by invasiveness, off-target toxicity, and insufficient therapeutic efficacy. Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has emerged as a promising strategy for spatiotemporally controlled cancer treatment. In this study, we developed NLS-functionalized semiconducting polymer nanoparticles (Pdots-NLS) by physically co-assembling PCPDTBT, PSMA, and the amphiphilic conjugate C18-PEG12-NLS through a simple nanoprecipitation method. The incorporation of C18-PEG12-NLS enhanced the intracellular accumulation of the nanoparticles in cultured cancer cells. Upon 808 nm laser irradiation, Pdots-NLS generated both reactive oxygen species and photothermal heating, enabling combined PDT and PTT. In vitro studies using three cancer cell lines showed that Pdots-NLS produced greater laser-induced cytotoxicity than non-functionalized Pdots. Furthermore, following intratumoral administration in a mouse xenograft model, Pdots-NLS combined with laser irradiation significantly suppressed tumor growth over 14 days without causing obvious changes in body weight or histopathological damage to major organs. These findings demonstrate that NLS functionalization provides a simple strategy for enhancing intracellular nanoparticle delivery and improving local combined photodynamic and photothermal cancer therapy.