Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad‐Spectrum Senotherapy

Abstract

Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and agerelated diseases. Canonical methods are generally designed to target SnC-associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor-made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs. The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad-spectrum SnCs, with high specificity over non-SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.

Three-Photon AIE Pt(II) Complexes as Cysteine-Targeting Theranostic Agents for Tumor Imaging and Chemotherapy

“…Lysosomes regulate apoptosis and cellular homeostasis . In cancer cells, lysosomes are more fragile and easily ruptured than normal lysosomes . As shown in Figure a, cancer cells (HeLa and HepG2) incubated with Lyso-Pt-CH 3 exhibit higher fluorescence intensity than normal cells (HUVECs and MH-S).…”

“…42 In cancer cells, lysosomes are more fragile and easily ruptured than normal lysosomes. 43 As shown in Figure 5a, cancer cells (HeLa and HepG2) incubated with Lyso-Pt-CH 3 exhibit higher fluorescence intensity than normal cells (HUVECs and MH-S). The above results are consistent with the results shown in Figure S35.…”

A senolysis-based theragnostic prodrug strategy towards chronic renal failure

“…[29][30][31][32][33][34][35][36][37] The recent years have also witnessed a rapid development of b-gal activable prodrugs as senolytics for the treatment of age-related diseases. [38][39][40][41][42] However, to the best of our knowledge, theragnostic prodrugs capable of senolysis and identifying SNCs are rarely reported, and there is no research on the construction of SA-b-gal activable prodrugs as senolytics for the treatment of CRF.…”

Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy

“…[9] To broaden the applicability of such senolytics, we also reported a prodrug-based senolytic by targeting the defective lysosome in senescent cells, showing the capability to eliminate different types of senescent cells. [10] Despite controlled drug activities, applications of these prodrugs are still limited as SA-β-gal is senescence-characterized, but not specified, which inevitably encounters unwanted "off-target" toxicities. [11] Since the target of senotherapy is the senescent cell, not a single molecule or signaling pathway, the combination of active cell targeting with multiple hallmarksbased drug activation is therefore imperative in order to yield more truly senolytic agents.…”

“…To tackle this issue, ever‐growing efforts have been engaged in a prodrug concept by engineering activatable senolytics to release toxic chemicals in response to the distinct features when cells undergo senescence, with a particular focus on senescence‐associated β‐galactosidase (SA‐β‐gal) [9] . To broaden the applicability of such senolytics, we also reported a prodrug‐based senolytic by targeting the defective lysosome in senescent cells, showing the capability to eliminate different types of senescent cells [10] . Despite controlled drug activities, applications of these prodrugs are still limited as SA‐β‐gal is senescence‐characterized, but not specified, which inevitably encounters unwanted “off‐target” toxicities [11] .…”