Supermolecularly assembled photochemotherapeutic nanocomposites composed of pure drug small molecules are promising for synergistically improved tumor therapy, yet potential multiple challenges remain to be addressed. Herein, we rationally designed a novel multifunctional small molecule disulfide modified natural pentacyclic triterpene of ursolic acid (UASS) that simultaneously possesses self-assembly ability, glutathione (GSH) responsivity, anticancer activity, biocompatibility and biodegradability and further constructed carrier-free GSH-sensitive photosensitive nanocomposite UASS-Ce6 NPs for safe and synergistically improved chemophototherapy. Specifically, UASS-Ce6 NPs exhibit improved 1O2 generation by reducing the energy gap (ΔEST) of Ce6 as determined by density functional theory. Meanwhile, molecular dynamics simulation revealed the possible reasons why free UASS self-assembles and UASS-Ce6 NPs with different assembled morphologies may be primarily attributed to the coplanar arrangement of UASS dimer units. Importantly, via noncovalent π-stacking and hydrophobic interactions, the resulting co-assemblies showed improved water solubility, increased intercellular ROS generation, desirable GSH sensibility, excellent biocompatibility, and enhanced tumor accumulation accompanied by rapid biodegradation, thus leading to significant in vitro and in vivo synergistic antitumor efficacy with favorable biosafety. This study provides a promising insight into the development of a self-assembled active single component platform with desirable stimuli responsiveness and biosafety toward synergistic antitumor therapy based on terpenoid natural small molecules.