Lysosomes are the “cell stomach” that digests various species including macromolecules and pathogens for self-repair and self-defense upon fusion with endosomes, autophagosomes, and phagosomes. Therefore, artificially manipulating intracellular vesicles could potentially promote lysosome-mediated intracellular digestion for disease prevention and treatment. Herein, a supramolecular strategy to efficiently tether and fuse acidic vesicles (i.e., lysosomes, late endosomes, autolysosomes, and phagosomes) has been developed for the first time to enhance the digestion of cellular wastes and foreign matter, including pathogens. A linear polyethylene glycol (PEG) derivative dually tagged with morpholine (MOR) and adamantane (ADA) on the opposite side, namely, MOR-PEG-ADA, was designed to target intracellular acidic vesicles via MOR and to decorate their surfaces with ADA. Subsequently, the addition of cucurbit[7]uril (CB[7]) grafted hyaluronic acid (HA) induced supramolecular tethering and fusion of acidic vesicles via strong host–guest interactions between CB[7] of CB[7]-HA and ADA residing on the surface of acidic vesicles. As a proof-of-concept, the overall cellular metabolism, including endogenous autophagy and the exogenous endocytosis and phagocytosis, was effectively upregulated, demonstrating that supramolecular regulation of the dynamics of intracellular acidic vesicles may promote the lysosome’s digestion to significantly improve cellular self-repair and self-defense.