Carrier-free nanoassembly of doxorubicin prodrug and siRNA for combinationally inducing immunogenic cell death and reversing immunosuppression

Abstract Doxorubicin (DOX) can elicit antitumor immunity responses by inducing immunogenic cell death (ICD) but also triggers upregulated expression of various immunosuppressive genes to counteract the ICD effect. To resolve this conflict, a carrier-free nanoassembly of acid-activatable DOX prodrug and small interfering RNA (siRNA) was developed to combinationally induce ICD and reverse immunosuppression. The carrier-free nanoassembly with rather high drug contents (4.13 % for siRNA and 21.67 % for DOX) was formed via cooperative π–π stacking and electrostatic interactions. The formed nanoassembly, termed as PEG@D:siRNA, possessed a well-defined nanostructure: a core consisting of DOX plus siRNA and a shell consisting of polyethylene glycol (PEG). It has been demonstrated that this carrier-free nanoassembly carrying siRNA targeting PD-L1 can significantly increase tumor-infiltrating T lymphocytes, improve interferon-γ (IFN-γ) expression, and ultimately strengthen the ICD effect of the DOX prodrug, resulting in a significantly enhanced anticancer immune response and superior tumor growth inhibition. In addition, carrier-free nanoassembly PEG@D:siRNA can also be conveniently extended as a general strategy to combine chemotherapy and immunotherapy, providing a facile avenue for improving cancer chemoimmunotherapy.