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Dense surface modification with short chain polyethylene glycol (PEG) has been previously demonstrated as favoring the transport of nanoparticles (NPs) across mucus. However, the ability of such approach to influence the distribution and retention of NPs along the length of the colorectum after rectal delivery has not been previously established. Herein, the distribution and retention of poly(lactic-co-glycolic acid) NPs modified with PEG in a non-covalent fashion are reckoned in a mouse model. Despite overall rapid depletion, both PEG-modified and non-modified NPs are able to reach the middle segment of the colon. PEG-modified NPs are able to enhance retention up to at least two hours post-administration, contrasting with nearly residual levels observed for non-modified NPs after 15min. The ability of PEG-modified NPs to putatively cross mucus also appears to promote association with tissues. Overall, the work provides significant insights as to the behavior of NPs in the colorectum, which could be valuable for the development of rectal nanomedicines. It further reinforces the potential usefulness of PEG-modified NPs as mucus-penetrating carriers for mucosal drug delivery.