A Programmed Cell‐Mimicking Nanoparticle Driven by Potato Alkaloid for Targeted Cancer Chemoimmunotherapy

Abstract Membrane camouflaged‐nanoparticles (CM‐NPs) have been exploited to inherit desired functionalities from source cells. Despite those advantages, membrane cloak may play a “double‐edged sword” role in tumor‐targeting therapy, as the intact membrane coating may hinder function‐exertion of loaded drugs after reaching predetermined site. Therefore, further optimization of CM‐NPs is still needed to enhance their delivery efficiency. Herein, natural product, Solamargine (SM), a cholesterol‐affiliative amphiphilic potato alkaloid is first applied as core component of “inner core,” to design a cell‐mimicking “core–shell” nanoparticle (RBC‐SLip) with acid‐responsive off‐coating properties for tumor‐targeted therapy. Owing to red blood cell membrane (RBCm)‐derived outer coating, it circulates stably in physiological conditions. While it would undergo an off‐coating morphological change in response to acid stimuli in tumor microenvironment (TME), afterwards, the resulting off‐coating liposome (SLip) shows active tumor‐targeting and endosomal escape abilities, thus contributing to superior antitumor efficacy. In addition, SM also possesses natural TME‐modulating ability; therefore, RBC‐SLip can synergize with the PD1/PD‐L1 blockade immunotherapy when encapsulated with PTX to achieve enhanced chemoimmunotherapy. The off‐coating strategy developed by natural products SM, provide a brand‐new perspective to optimize CM‐NPs, and it also embodies application value of “unification of medicines and excipients” of natural products.