Co-assembly of natural small molecules into a carrier-free hydrogel with enhanced synergism for pancreatic cancer theranostic amplification.

Pancreatic cancer is one of the most devastating solid tumors and lacks ideal therapeutic options. The efficiency of using classic chemotherapeutic agents like gemcitabine (GEM) solely has been limited immensely owing to severe resistance and systemic toxicity, thus necessitating alternative multi-pronged strategies. Multicomponent supramolecular co-assembly leveraging natural small molecules (NSMs) cannot only produce carrier-free hydrogel materials having superior mechanical properties for convenient administration, but also achieve optimal synergies in combinational drugs therapy. Herein, a natural structural analog of GEM with favorable pro-apoptotic effect, adenosine (Ado), was found firstly to self-assemble spontaneously into a hydrogel (Ado-gel). Sequentially, we constructed a novel two-component hydrogel (DA-gel) via co-assembling Ado with another NSM evidenced here as new autophagy inhibitor, gentisic acid (2,5-dihydroxybenzoic acid, DHB). Addition of DHB had reinforced the thermal-responsiveness and viscoelasticity evidently in DA-gel, which ascribed to the heightened intermolecular hydrogen bonding and π-π stacking interactions. Together with its good injectability and biosafety, the local injection can be conducted smoothly so as to improve the compliableness of patients in clinical settings. More intriguingly, DA-gel was proven to exhibit the best anti-tumor efficiency in pancreatic carcinoma comparing with corresponding single-component and mixture