Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

Poor permeation of drugs and "immune-cold" tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment. Here, light-activated penetrable nanoparticles (PEG-VAL&DOX&ICG@RNPs) for co-delivery of the chemotherapeutic drug doxorubicin (DOX), the photosensitizer agent indocyanine green (ICG), and the angiotensin II receptor blockers valsartan (VAL) were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor. Studies showed that under the first-wave of laser irradiation, the polyethylene glycol (PEG) hydrophilic layer as an "inert" surface could detach from the nanoparticles, release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway. When exposed to the second-wave of laser irradiation, the synergistic chemo-photo-immunotherapy can be achieved. As expected, in 4T1 tumor-bearing mice, PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors, down-regulate α-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors, induce dendritic cells (DCs) maturation, and promote intratumoral infiltration of cytotoxic T lymphocytes. Moreover, combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo. This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of "immune-cold" solid tumor treatment.