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The tumor penetration and accumulation of nanoparticle-based drug delivery systems are highly dependent on the particle size. Nanomedicines in the sub-100 nm range have been suggested by previous studies to have superior antitumor efficacy on various solid tumors. SN-38 is a very important and highly potent drug for several cancers including colon cancer. However, due to the ultra-flat aromatic structure of SN-38, it is typically very difficult to produce sub-100 nm, SN-38-encapsulated nanoparticles without modification of the chemical structure. Here, we report on the successful production of 20–30 nm, SN-38-encapsulated photonic micelles for effectively trimodal cancer therapy. Taking advantages of the supramolecular “π-π” stacking and hydrophobicity interaction between SN-38, and a unique class of photonic nanoporphyrin micelles (NPM), the extremely hydrophobic SN-38 was successfully encapsulated into NPM with significantly increased water solubility (up to 500 times). At equivalent dose of drug, photosensitizer and light irradiation, combination therapy with SN-38-encapsulated nanoporphyrin micelles (SN-NPM) enhanced the in vitro antitumor activity by 78 and 350 times over single treatment with SN-38 and phototherapy alone, respectively. Due to the relatively small size, SN-NPM possessed superior long tumor retention time (>5 days) and much higher accumulation in tumors than in normal organs, as shown by near-infrared fluorescence (NIRF) imaging. Furthermore, the trimodal therapy (photothermal-, photodynamic- and chemo-therapy) with SN-NPM demonstrated dramatically enhanced in vivo antitumor efficacy over single treatment on nude mice bearing HT-29 colon cancer xenograft. Therefore, these sub-100 nm, SN-38-encapsulated photonic micelles show great promise for multimodal cancer therapy.