Eliciting immunogenic cell death via tumor-associated fibroblast inactivation and autophagy induction with doxorubicin and silybin loaded molecularly imprinted nanosystem

The use of immunogenic cell death (ICD) inducers has potential to potentiate anti-tumor immune responses in clinical treatment. However, its effectivenes is greatly hampered by the limited accessibility of ICD-inducing agents to cancer cells and inadequate immunogenicity induced by a single ICD-inducer. In this research, the doxorubicin (DOX) and silybin (SLN) loaded lactate dehydrogenase A (LDHA)-imprinted biodegradable silica nanoparticles (LDHA@MIP-DSD) is designed to access cancer cells and boost ICD effect for cancer immunotherapy. LDHA, overexpressed by 4T1 cells, can stimulate tumor-associated fibroblasts (TAFs) activation and further hinder drug infiltration within tumor sites. LDHA@MIP-DSD is constructed by surface imprinting with LDHA as imprinting template, which produces high specificity and potent inhibitory effects towards LDHA activity, and thus reducing TAFs activation, remodeling extracellular matrix (ECM) and ultimately enhances the accessibility of nanodrugs to cancer cells within tumors. After entering tumor cells, LDHA@MIP-DSD responds to the intracellular redox environment, leading to the simultaneous release of the encapsulated drugs. SLN, as a powerful autophagy enabler, induce tumors autophagic death and achieved strongest antitumor immune responses when the molar ratio of DOX and SLN is 2:1. LDHA@MIP-DSD treatment significantly produces a 11-fold increase of CD8+T cells and facilitates their infiltration of cancer cells in tumors. Moreover, LDHA@MIP-DSD possesses prominent therapeutic effects of palliatort tumor growth and prolongs survivals in 4T1 tumor model. Since the specific LDHA shielded by molecularly imprinting and autophagy induced by SLN, LDHA@MIP-DSD exhibits optimal immune stimulation and antitumor efficiency due to its enhanced ICD effect, providing the new horizons for immunotherapy.