Synthetic Protein Circuits for Programmable Cell Death Control
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Solution Overview
Problem
Current cell-killing approaches cannot fully direct the mode of cell death, lacking the ability to controllably induce apoptosis or pyroptosis and tune their relative frequencies in various cell contexts.
Innovation Solution
Development of synthetic protein circuits that allow activation and repression of both apoptosis and pyroptosis, enabling tailored control of cell death by integrating and computing multiple input signals to selectively kill target cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If pyroptosis is induced to enhance anti-tumor immunity, then cell killing efficiency is improved, but pathological inflammation occurs
Solution Approach 1:
The patent implements dynamic control of cell death mode by using inducible promoter systems (e.g., tetracycline-responsive, doxycycline-inducible) to regulate the expression of pyroptosis effectors like GSDMD. This allows the system to adapt between apoptosis and pyroptosis based on external signals, achieving high cell killing efficiency when needed while minimizing pathological inflammation through controlled activation
Solution Approach 2:
The patent changes the parameter of cell death mode by using small molecule inducers (doxycycline, tetracycline) to switch between apoptotic and pyroptotic pathways. By adjusting the concentration and timing of these inducers, the system can precisely control the比例 of apoptosis versus pyroptosis, optimizing tumor cell killing while reducing harmful inflammation
2Reliability
If existing cell-killing approaches are used, then cell death is induced, but the mode of cell death cannot be fully directed
Solution Approach 1:
The patent segments the cell death control system into distinct modular pathways: one module for apoptosis (using caspases, BAX, BID) and another for pyroptosis (using GSDMD, gasdermin family proteins). Each module can be independently regulated by specific promoter systems, allowing reliable induction of either death mode while providing versatile control over the proportion and timing of each pathway
Solution Approach 2:
The patent creates a universal control platform that can direct both apoptosis and pyroptosis through common regulatory elements. The use of inducible promoters and small molecule triggers provides a multi-functional system that can respond to various input signals (doxycycline, tetracycline, other inducers) to control multiple cell death outcomes, enhancing both reliability and adaptability
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The synthetic protein circuits achieve controlled induction of apoptosis or pyroptosis, allowing for selective killing of target cells and potentially enhancing anti-tumor immunity while minimizing pathological inflammation.
Implementation Method 1
a first heterologous protease in a first heterologous protease active state is capable of cutting the first heterologous protease cleavage site of the first apoptosis polypeptide
Data Source
AI summary
Disclosed herein include methods, compositions, and kits suitable for use in programmable cell death control. Compositions (e.g., nucleic acid compositions, synthetic protein circuits) provided herein can comprise one or more apoptosis polypeptides; and/or one or more pyroptosis polypeptides; and/or one or more input polypeptides. In some embodiments, expression of a synthetic protein circuit of the disclosure can induce, e.g., apoptosis and/or pyroptosis in a cell.