A porphyrin-HDL nanoparticle for low-dose photodynamic therapy-induced antitumor immune activation

Photodynamic therapy (PDT) is a clinically translatable modality that uses a photosensitizer, oxygen, and light to induce tumor cell death and antitumor immunity. Porphysome-based nanoparticles (LC-ePS) act as photosensitizers and accumulate in the tumor vasculature and extracellular matrix at a 3-hour drug-light interval (DLI). LC-ePS-mediated PDT induces robust systemic immunity, including durable antitumor memory that protects against tumor rechallenge. This is compared to immunodeficient NSG mice where LC-ePS PDT lost therapeutic efficacy, indicating that durable tumor control requires functional host immunity. However, the efficacy of conventional nanoparticles is limited by their poor tumor penetration and perivascular sequestration, which restricts direct tumor cell ablation and subsequent immune activation. To address this, porphyrin-HDL nanoparticles (PLP) were engineered with a markedly smaller size. At ~20 nm, this platform enables deeper penetration into tumors with rapid cellular uptake, enhancing PDT efficacy. PLP nanoparticles were synthesized via an HDL self-assembly approach with porphyrin lipids, maintaining photoreactivity while minimizing size. In BALB/c mice bearing CT26 tumors, PLP were administered intravenously, and varying PDT light doses were applied to determine the minimal fluence for complete ablation. PLP demonstrated markedly enhanced photodynamic potency compared with LC-ePS. Whereas LC-ePS at10mg/kg required 135 J/cm² at a 3-hour DLI to achieve complete tumor ablation, PLP achieved full tumor eradication at a 2.5-fold lower drug dose (4mg/kg) and with >2.5-fold lower light dose (50 J/cm²). These dose-reduction suggest that the superior PDT efficacy of PLP arises from its enhanced intracellular uptake and improved tissue penetration, collectively offering higher photochemical efficiency in vivo. Overall, the PLP nanoplatform represents a significant advance in photodynamic therapy, offering deeper tumor penetration, markedly reduced therapeutic doses requirement, and strong immunomodulatory potential. Together, these features position PLP as a promising strategy for integrating effective local tumor ablation with robust systemic antitumor immunity. Ongoing work is focused on further optimizing in vivo innate immune activation and adaptive T-cell responses.