Tumor heterogeneity and drug resistance have been invincible features of cancer for its complete cure. Despite the advent of immunotherapy, the expansion and diversification of cancer cells evolved even in the absence or presence of drug treatment discourage additional therapeutic interventions. For the eradication of cancer cells, therefore, an 'all-at-once' strategy is required, which exploits both target-selective chemotherapy and non-selective physicotherapy. Multifactorial microcapsules comprising gold nanoparticles (AuNPs) and a self-assembly protein of α-synuclein (αS) were fabricated, in which hydrophobic and hydrophilic drugs could be separately encapsulated by employing lipid-based inverted micelles (IMs). Their combined physicochemical therapeutic effects were examined since they also contained both membrane-disrupting IMs and heat-generating AuNPs upon irradiation as physicotherapeutic agents. For the optimal enclosure of IMs containing hydrophilic drugs, a porous inner skeleton made of poly(lactic-co-glycolic acid) was introduced, which would play the roles of not only compartmentalizing the internal space but also enhancing proteolytic disintegration of the microcapsules to discharge and stabilize IMs to the outside. In fact, hydrophobic paclitaxel and hydrophilic doxorubicin showed markedly enhanced drug efficacy when delivered in the IM-containing microcapsules exhibiting the 'quantal' release of both drugs into the cells whose integrity could be also affected by the IMs. In addition, the remnants of αS-AuNP microcapsules produced via proteolysis also caused cell death through photothermal effect. The multifactorial microcapsules are therefore considered as a promising anti-cancer drug carrier capable of performing combinatorial selective and non-selective chemical and physical therapies to overcome tumor heterogeneity and drug resistance.