Nanoscale liposomes are widely recognized as promising drug delivery materials; yet, their utilization in oral drug delivery has been hindered by their limited ability to efficiently penetrate the intestinal mucus layer. Herein, we present an approach to enhance oral drug delivery and improve the mucus penetration capability of liposomes by conjugating bromelain, a mucolytic enzyme derived from pineapple stems, to the liposome membrane (Bro-Lip). With an optimized bromelain payload of 11.1 nmol/mg, we achieved an impressive 47.8% conjugation efficiency while retaining 77.5% of the proteolytic activity post conjugation. Physicochemical analysis revealed that Bro-Lip measured 152.8 nm in size with a ζ potential of −2.3 mV. Notably, Bro-Lip exhibited a significantly enhanced capacity to penetrate the porcine mucus layer, demonstrating a 2.87-fold improvement compared with bare liposomes. Furthermore, we assessed the transcellular permeability of Bro-Lips using Caco-2 and Caco-2/HT29 coculture models, revealing substantial enhancements in permeability compared to unmodified liposomes. Specifically, in Caco-2 cell monolayers, mucus permeability increased by 3.80-fold, while in Caco-2/HT29 cocultures, it rose by 2.25-fold. Additionally, Bro-Lip demonstrated an improved cellular uptake in Caco-2 cells. These findings highlight the potential of Bro-Lip as an effective oral delivery system by enhancing mucus permeation and cell membrane permeation.