Biomineralized Albumin-Macrocyclic Conjugates for Synergistic Metal Ion-Based Combination Therapy in Cancer Treatment

Metal ion-based combination therapy holds great promise for cancer treatment. However, current codelivery systems often suffer from poor biocompatibility-associated severe side effects. Inspired by natural biomineralization processes, we developed biomineralized albumin-macrocyclic conjugates (BAMC) as a codelivery platform for metal sulfides and small-molecule drugs. In this system, bovine serum albumin (BSA) guides the biomineralization of metal sulfides, while surface-conjugated sulfonate azocalix[4]arenes (SAC4A) enable the precise loading of small-molecule therapeutics. Upon reaching tumor tissues, SAC4A is enzymatically degraded and the metal sulfides are converted into bioactive ions, enabling the simultaneous release of therapeutic agents. Using this strategy, BAMC enabled the codelivery of Cu²⁺ and an HSP90 inhibitor (BIIB021), as well as Zn²⁺ and an autophagy inhibitor (hydroxychloroquine, HCQ), leading to efficient combination photothermal therapy and cancer immunotherapy in 4T1 tumor-bearing mice. Given the broad applicability of biomineralization techniques to various metal ions and the wide-ranging inclusion capabilities of SAC4A for different drugs, BAMC represents a promising platform for metal ion-based combination therapies.