ABSTRACT The next‐generation anti‐cancer therapeutics must disrupt intracellular mechanics, efficiently eradicating cancer cells, rather than simply intoxicating them. We evaluate the mechanism of action of PCMS, a PAMAM‐based supramolecule that eradicates cancer cells by reorganizing their internal mechanics rather than their genes. Once internalized, PCMS self‐assembles into a perinuclear ring that severs nucleus‐cytoskeleton communication. We observed PCMS's dual‐intelligent mechanisms of action: Cytoskeletal rescue, where actin‐microtubule filaments move towards the PCMS ring, treating it as a surrogate plasma membrane, attempting to restore vesicular trafficking; Nuclear counter‐expansion, where chromatin‐lamina condensates undergo stepwise viscoelastic transitions that push the nuclear envelope outward to reestablish membrane contact. These contradictory forces amplify mechanical stress, driving super‐critical strain and nuclear lysis without broad transcriptional modulations. By geometry alone, PCMS collapses the actin‐microtubule‐nucleus continuum and turns the cell's adaptive machinery into its own executioner. The discovery that life and death decisions can be reprogrammed through spatial conflict establishes a paradigm of mechanical deception, inaugurating a new class of cellular adaptive feedback‐targeted mechanotherapeutics that overcome resistance by exploiting the cell's own morphogenetic logic.
Dey et al. (2026) studied this question.